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The profound pharmacological attributes of macrocyclic compounds have spurred their transformation into pharmaceutical drugs. Within conformationally pre-organized ring structures, the macrocycle’s intricate functions and stereochemical complexity contribute to a heightened affinity and selectivity for protein targets. Simultaneously, they maintain sufficient bioavailability to penetrate intracellular locations. As a result, the construction of macrocycles emerges as an optimal strategy for addressing the challenge of “undruggable” targets like cancer. Cancer stands as the second most prevalent and formidable threat to human life, prompting researchers to channel their efforts toward the extraction and synthesis of effective therapeutic drugs designed on macrocyles to combat various types of cancer cells. Many macrocyclic drugs have been licensed by the Food and Drug Administration (FDA) for the treatment of cancer patients. Nonetheless, the significance of these compounds in the production of cancer therapeutics is still undervalued. According to recent research, macrocyclic compounds can be a useful tactic in the fight against drug resistance in the treatment of cancer. This chapter aims to present bits of evidence about the uses of macrocyclic compounds as potential cancer treatments. By providing more innovative approaches to aid cancer patients and society as a whole, this chapter will hopefully stimulate greater interest in the development of macrocyclic medicines for cancer therapy.
Department of Chemistry, The Women University, Multan, Pakistan
Samina Aslam
Department of Chemistry, The Women University, Multan, Pakistan
Ali Irfan*
Department of Chemistry, Government College University Faisalabad, Faisalabad, Pakistan
Emilio Mateev
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Medical University, Sofia, Bulgaria
Sami A. Al-Hussain
Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
Magdi E.A. Zaki*
Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
*Address all correspondence to: raialiirfan@gmail.com and mezaki@imamu.edu.sa
1. Introduction
Macrocycles have been referred as a ring structure containing 12 or more atoms [1]. Although there are differences of opinion regarding the ring size criteria for defining macrocycles, this alternative highlights the qualitative differences in behavior between large macrocyclic rings (≥12 atoms) and medium rings (8–11 atoms). Because of their constrained rotation, macrocycles have a structure that allows for some conformational pre-organization. Numerous naturally occurring compounds possess a macrocyclic core, indicating that the synthesis of secondary metabolites derived from these scaffolds could confer an evolutionary benefit [1, 2]. Macrocycles can belong to a variety of classifications, such as peptidic and nonpeptidic natural products, synthetic peptides and non-natural macrocycles [3]. Repeating patterns in the distribution of charge and polarity within the molecule are a significant feature of many macrocycles. A polar, hydrophilic side and an apolar, lipophilic side are present in many structures. A general structure A with an endocyclic small heterocycle is often accompanied by another small heterocyclic (such as an oxazole, imidazole, thiazole, sugar, etc.) or substituted aromatic moiety, which may be endo- or exo-cyclic (Figure 1) [2].
Figure 1.
A distribution of polarity domains present in numerous natural macrocycles [2].
Macrocycles have physicochemical and pharmacokinetic characteristics similar to those of drugs, including high lipophilicity, solubility, bioavailability and metabolic stability. Macrocyclic substances have demonstrated therapeutic potential, however their potential for discovering new medicinal molecules has been under-explored and inadequately studied. There are numerous causes for this. The pharmaceutical industry has been reluctant to explore natural products more and more because of the challenges they pose in the analogue synthesis process due to their structural complexity. Additionally, it is now common practice to screen compounds that comply with the rule of 5-compliant compounds preferentially. Nonetheless, a number of research organizations are looking at the possibility of using synthetic macrocycles for drug discovery, and they have demonstrated that these substances can offer good target selectivity and affinity in structures with acceptable drug-like characteristics. There are currently several synthetic macrocycles undergoing active preclinical and clinical research that have no relation to natural compounds [1]. There are known to be more than 100,000 secondary metabolites of natural products, and about 3% of these are macrocycles [2]. Although the proportion of macrocycles in this class of natural products is small, it contains a potent subset of medicines that are used to treat cancer, combat emerging infectious pathogens, and modify immune system responses. A number of cancer medications that are either approved for clinical use or have advanced to the late stages of clinical development are the result of the exploitation of natural product macrocycles.
2. Advantages of using macrocyclic molecules as drugs
The use of macrocyclic compounds as pharmaceuticals has several benefits: First, in order to manage their structural flexibilities, macrocyclic molecules often have more limited conformations. Strong binding affinities and excellent selectivity to target proteins are made possible by their tight conformations. Second, compared to conventional small-molecule medicines or large biologics, macrocyclic compounds have unusual pharmacological properties due to their unique structural features [4]. Through macrocyclization, molecules can lose some of their degree of freedom, which can improve their oral bioavailabilities, cellular penetration, polarity, metabolic stabilities, and pharmacokinetic and pharmacodynamic properties [1, 3, 5, 6]. Macroscopic molecules have molecular weights ranging from 300 to 2000 Dalton. They often have molecular weights that are lower than acyclic peptides, which typically have molecular weights of more than 2000 Dalton. Their lifetime in vivo is increased by their decreased molecular weights, which also provide more effective pharmacological properties, such as permeabilities and reduced susceptibility to proteolytic breakdown [7]. Moreover, macrocycles are the tiniest examples of biomolecules with functional sub-domains; they are not merely larger forms of tiny molecules [1]. In summary, throughout the past 20 years, medicinal chemistry has focused a lot of attention on macrocyclic molecule medicines due to their many benefits.
The second most prevalent disease that poses a threat to human life is cancer. The prevalence of cancer is rapidly rising in the whole world [8]. In 2022, there were 0.6 million cancer-related fatalities and 1.9 million new cancer diagnoses in the US, according to cancer statistics [9]. The annual cost of cancer is likewise very high. Thus, there is a large global market for cancer medications, and their sales are high. Thus, there is a great deal of interest in drug research to develop different cancer therapies. Researchers have recently concentrated their efforts on creating effective medicines that can treat various cancer cells. The majority of research has gone toward creating medications that treat cancer in its early stages, as these medications have attracted more attention than those that treat the disease in its later stages [10]. Numerous macrocyclic compounds, including pacritinib, have demonstrated efficacy as medications for the treatment of cancer patients. Several efforts have been undertaken to create innovative macrocyclic drugs to treat cancer patients, as the unmet demands for cancer therapy in clinics continue to rise. For the purpose of developing possible anticancer derivatives, macrocyclic molecules are typically preferred, particularly in the chemical, biological, and medicinal domains [6, 11].
3. Why macrocylic compounds are used as anti-cancer agents?
Targeting proteins with expanded binding sites, like class B G-protein-coupled receptors (GPCRs), protein-protein interactions, and certain enzymes, is a very challenging task for small molecule drug developers [12]. Designing anticancer drugs presents especially challenging conditions. The most widely used “biological agents” to modulate these targets have a number of drawbacks, such as high cost, low oral bioavailability, lack of cell permeability, and decreased patient compliance. Due to their degree of structural pre-organization, macrocyclic compounds minimize the significant entropy loss during binding by enabling important functional groups to interact across extended binding regions in the protein [3]. A molecule must take on a bioactive shape in order to bind to a target protein. Because the ligand-protein binding reduces the number of conformations the unbound molecule can adopt, there is a lower entropic cost. Macrocycles are conformationally confined, yet not totally stiff, with limited internal bond rotations. Macrocycles are theoretically adaptable compounds that possess sufficient flexibility to effectively engage with flexible binding sites in proteins while also reducing the internal entropy loss linked to the ligand’s transition from the unbound to the bound state. A decrease in a receptor’s entire mobility can have a positive enthalpic contribution even though it is an unfavorable entropic alteration because it can strengthen hydrogen bonding and other intermolecular interactions with a ligand. Because of these properties of macrocyclic molecules, “molecular macrocyclization” is an important strategy for resolving the aforementioned issues [13]. Consequently, further research should be done on the relationships that macrocycles have with the proteins that they target [13].
3.1 Role of macrocycles in diseases especially in cancer and cancer multi drug resistance (MDR)
The primary therapeutic indication for which macrocyclic drugs are used (representing 44.4% of all macrocyclic pharmaceuticals) is an infectious disease. While antibacterial agents make up the majority of this class, antifungals (8.3%) and antivirals (6.9%) are also significant. The remaining three primary therapeutic indications are immunosuppressants (5.6%), autoimmune diseases (5.6%), and oncology (20.8%). 13 “Other” minor indications, or 23.6% of the total number of indications, also employ macrocyclic drugs. Antidiuretics, persistent pain, hereditary obesity, heart failure, etc. are some of these indications. Table 1 provides a comprehensive list of therapeutic indications and targets for the macrocyclic medicinal products [14].
FDA-approved macrocyclic drugs and their related targets therapeutic indicationsa.
NA: Target not available.
Natural products or rational innovations are potential sources of macrocyclic compounds. The majority of clinical prospects and macrocycles that have been approved by the Food and Drug Administration (FDA) are obtained as natural products due to their complicated synthetic design [14, 15]. One well-known example of a macrocyclic molecular drug is erythromycin. It provides people with penicillin allergies with additional options by efficiently treating Gram-positive bacterial infections [16]. Many macrocyclic compounds have since been created to treat a wide range of maladies. Biologically active macrocycles have become more common in medicinal chemistry literature over the last few years [1, 6]. Scheme 1 illustrates a few examples of biologically active macrocyclic compounds which possess medical importance (Figure 2) [2].
Figure 2.
Some naturally occurring macrocycles displaying a variety of medicinally important biological activities.
Drug resistance, pharmacological ineffectiveness and systemic toxicity of given medications are common challenges related to cancer therapy [17]. It is also very important to find new anticancer agents as pharmacological leads because confusing characteristics such the numerous signaling nature of pathways and the propensity of most cancer cells to change have impeded the search for an effective therapeutic agent to treat cancers [18]. Multi-target macrocyclic inhibitors are one way to get beyond these obstacles and succeed in the battle against different types of cancer.
Targets that have proven extremely difficult for conventional small-molecule drug development have been repeatedly successfully targeted by macrocycles, particularly when it comes to modifying macromolecular processes like protein–protein interactions. Macrocycles are useful for controlling a variety of macromolecular interactions; frequently, they do this by giving their targets additional interaction surfaces that might lead to a complex’s gain-of-function that is dependent on the macrocycle. The potential of several types of macrocyclic natural products to alter the dynamics of microtubules in mammalian cells and impede the growth of tumors is presently being studied [19]. Once more, the α and β subunits of the tubulin heterodimer modify the protein-protein interactions responsible for these effects. Epothilone B, a macrocycle originating from myxobacteria, connects itself at the tubulin subunit interface (a region that is shared by the taxol binding site). Widespread reorganization of the α–β junction disrupts general microtubule dynamics while stabilizing the dimer [20]. Ixabepilone has been licensed for the treatment of metastatic breast cancer [21]. Although there are numerous examples of non-macrocyclic microtubule disruptors, the state of our knowledge suggests that macrocycles are widely found in nature and are used to modify protein–protein interactions between microtubule subunits.
Figure 3 displays the extracellular proteins that are targeted by macrocyclic peptides, the associated signaling pathways, and their physiological roles. The hepatocyte growth factor (HGF)-mesenchymal-epithelial transition tyrosine kinase receptor (MET) interaction is essential for cancer cell proliferation, migration, and invasion. HiP-8 (Receptor tyrosine kinase (RTK) inhibitors) can disrupt this connection (Figure 3a). C-X-C chemokine receptor (CXCR4) antagonists such as motixafortide, balixfortide, LY2510924, and Pep R54 can block the connection between CXCR4 and CXCL12, which is necessary for the growth of cancer cells (Figure 3b). Somatostatin analogs include pasireotide and lanreotide. To stop cell division, they can prevent endogenous somatostatin from activating somatostatin receptors (Figure 3c). The interaction between programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1), which negatively modulates the adaptive immune systems, can be inhibited by BMSpep-57,77,99, BMS-986189, and C8 (inhibitory immune checkpoint inhibitors). D4–2 has the ability to block the connection between CD47 and SIRPα, which releases a “do not eat me” signal that prevents immune cells from identifying and eliminating cancer cells. For cancer immunotherapy, the PD-1/PD-L1 and CD47/SIRPα domains are essential elements (Figure 3d). Hedgehog (HH) signaling protein inhibitors, such as HL2-m5, can prevent the HH pathway from activating, which controls the expression of target genes (Figure 3e) [22].
Figure 3.
Extracellular protein–protein interactions targeted by macrocyclic compounds [22].
4.1 Macrocyclic compounds targeting cancer development and to overcome drug resistance
The development of cancer is characterized by 14 key functional features, as stated in the new hallmarks of cancer [23]. Numerous proteins that are essential to various cancer pathways have been effectively targeted by macrocyclic compounds. Among these targets are histone deacetylase (HDAC), cyclin-dependent kinases (CDKs), Janus kinase (JAK2), and mammalian target of rapamycin (mTOR). However, patients with cancer now have a higher quality of life thanks to targeted therapy, particularly those with nonsmall cell lung cancer (NSCLC). It has been demonstrated that macrocyclic compounds are effective cancer treatment agents. From 2007 to 2022, the US FDA authorized nine macrocyclic medications for use in cancer patients (Table 2). Several drugs target essential proteins implicated in the genesis of cancer. For instance, Ribulin (Halaven) was authorized in 2010 for the treatment of patients with liposarcoma and in 2010 for patients with fatal or metastatic breast cancer. In 2014, Lorenotide received approval for the treatment of gastroenteropancreatic neuroendocrine tumors, or GEP-NETs. In 2020, the FDA authorized Libirectedin (a macrolide) for the treatment of SCLC. The FDA authorized paritinib in 2022 to treat MF, a rare form of leukemia.
Table 2.
Macrocyclic drugs approved by FDA (2007–2022) for cancer therapy.
FDA, Food and Drug Administration; RCC, renal cell carcinoma; MW, molecular weight.
Targeted therapy’s long-term success is limited by drug resistance that eventually developed in cancer patients after these medications were first used. When it comes to combating drug resistance, particularly pocket-alteration-mediated drug resistance, macrocyclic compounds exhibit more potency than acyclic molecules due to their smaller and more compact structures. Patients with NSCLC who have activating EGFR mutations and fusion proteins containing tropomyosin receptor kinase (TRK) or anaplastic lymphoma kinase (ALK) are successful cases. To avoid confusion, only macrocyclic compounds that can inhibit kinases with acquired resistance mutations were included in this category. This is because several drug targets that are crucial for the development of cancer are also involved in the drug resistance for other target proteins. For instance, patients who have drug resistance from EGFR-targeted therapy may benefit from a combination of mTOR inhibitors due to enhanced mTOR signaling [36].
The FDA approved a single macrocyclic compound to overcome drug resistance in cancer-targeted therapy. Lorlatinib is a small, compact drug with good brain penetration that potently suppresses the growth of resistant malignancies that have relapsed after earlier-generation therapy. In order to overcome resistance to the previous generation of acyclic ALK-specific inhibitor medicines, lorlatinib was licensed (2018) for the treatment of ALK-positive NSCLC [36]. SB1578 and zotiraciclib, two novel JAK2 inhibitors that target the development of cancer, as well as novel inhibitors of ALK, TRK, and EGFR that target the development of drug resistance to targeted therapy, are now in the exploratory stage. Several newly created substances are still in the preclinical phase. The EGFR inhibitor BI-4020, for instance, has not yet been the subject of any published clinical trials. Phase 1 or phase 2 clinical trials are now in progress on a number of these compounds. Repotrectinib, for instance, inhibits a number of ALK, ROS1, and TRK kinase resistant mutant proteins. To investigate the effectiveness of repotrectinib in patients with solid tumors, six clinical trials are presently accepting new participants; the majority of these trials are in phase 1 or phase 1/2. Patients with advanced solid tumors containing ALK, ROS1, and NTRK1–3 rearrangements (TRIDENT–1) are enrolled in an ongoing phase 1/2 clinical trial (NCT03093116). Patients who had relapsed on repotrectinib but were TKI-naïve or NTRK+ had durable responses [37]. The discovery of macrocyclic compounds, such as zotizalkib, repotrectinib, lorlatinib, and BI-4020 illustrates the substantial advantages of macrocyclic drugs in enhancing affinity and selectivity in overcoming drug resistance, owing to their powerful actions against resistant proteins. Historically, drug development has relied more on logical design than on random screening. The rational design of macrocyclic structures accelerates the process of discovering novel drugs. Table 2 lists the macrocyclic compounds that are used to target the development of cancer and to combat drug resistance in cancer cells.
Many synthetic and naturally occurring macrocyclic anticancer drugs are now in use, and others are continually being sought after [38].
5.1 Natural macrocyclic anti-cancer agents
Natural products have long been used for medical purposes [39]. Natural products have proven enormously beneficial in the treatment of cancer. The two most well-known of these are taxol from Taxus baccata, which is used to treat cervical cancer, and the vinca alkaloids from Catharanthus roseus (Vinca rosea), which are used to treat leukemia [40, 41]. Thus, natural chemicals from plant, soil, marine, fungal, and animal sources cannot be ignored in the quest for multitarget anticancer agents. For example, one naturally occurring macrocyclic drug that has shown strong inhibition against various cancer cell types is rapamycin.
5.1.1 Natural macrocycles as anti-colon and anti-cervical cancer agents
Sea squirt depsipeptides are known as didemnins. They are active against B16 melanoma and P388 lymphocytic leukemia, among other malignancies [42]. It has been reported that didemnins B (Figure 4) target DNA functioning [43]. Through the combined suppression of eukaryotic translation elongation factor-1α (EEF1A1) and palmitoylprotein thioesterase 1 (PPT1), it disrupts the cell cycle and prevents DNA synthesis at the elongation phase [44]. Moreover, it inhibits protein synthesis by blocking the translocation required for eukaryotic elongation factor (Eef-2) and activates caspases, which triggers apoptosis [45].
Figure 4.
Structure of Didemnin B acting as an active anti-colon and anti-cervical cancer agent.
5.1.2 Natural macrocycles as anti-renal cell cancer agents
Temsirolimus (Figure 5) is an analog of rapamycin, a natural substance. For the treatment of adult patients with advanced RCC, temsirolimus is prescribed. The enzyme that controls cell growth and proliferation, known as mTOR, is inhibited by temsirolimus (Torisel®; Wyeth Pharmaceuticals, Inc., Madison, NJ). Through mTOR inhibition, temsirolimus stops cells from progressing from the G1 to the S phase of the cell cycle. It also inhibits mTOR-dependent protein translation, which is triggered by growth factor stimulation of cells, which has an impact on cell proliferation [24].
Figure 5.
Structure of Temsirolimus acting as an anti-renal cell cancer agent.
5.1.3 Natural macrocycles as anti-pancreatic and anti-pulmonary cell cancer agents
Cyclic hexapeptides from a deep-water sponge belonging to the species Microscleroderma are known as microsclerodermins [46]. Microsclerodermin A and B (Figure 6) inhibit the transcriptional activity of NF-κB, which results in a decrease in the amount of phosphorylated (active) NF-κB (nuclear factor kappa B) cells in the AsPC-1 cell line. Additionally, they significantly induce apoptosis in the AsPC-1, MIA PaCa-2, BxPC-3, and PANC-1 pancreatic cancer cell lines. The expression of proteins in the glycogen synthase kinase 3 pathway was likewise controlled by these anti-cancer agents according to further research into their mode of action [47].
Figure 6.
Structure of Microsclerodermim acting as an anti-pancreatic and anti-pulmonary cell cancer agent.
5.1.4 Natural macrocycles as anti-prostate cancer cell agents
A trisoxazole macrolide called halichondramide (Figure 7), is derived from the marine sponge Chondrosia corticate. A range of cancer cells are resistant to its antiproliferative properties. For example, it modulates the epithelial-tomesenchymal transition, which results in an antimetastatic impact on human prostate cancer cells. HCA had a strong inhibitory effect on PC3 cell growth, with an IC50 of 0.81 μM. This compound has cytotoxic effects via suppressing the Akt/mTOR pathway, and it blocks the G2/M phase by upregulating the expression of the proteins GADD45 and p53 [48].
Figure 7.
Structure of Halichondramide acting as an anti-prostate cancer cell agent.
5.1.5 Natural macrocycles as anti-brain cell cancer agents
A polyketide called Candidaspongiolide (Figure 8) was isolated from Candidaspongia sp. In both U251 and HCT116 cells, it suppresses protein synthesis and triggers apoptosis, with the latter occurring partly through a caspase 12—dependent mechanism [49]. Furthermore, this compound selectively suppresses the proliferation of human melanoma cells in contrast to cell lines of lung and breast cancer [50].
Figure 8.
Structure of Candidaspongiolide acting as an anti-brain cell cancer agent.
5.2 Synthetic macrocycles
The following examples show that synthetic macrocycles can offer disease-relevant targets appealing ligands, with these compounds offering drug-like stability and bioavailability together with high levels of target affinity and selectivity. Recent research has focused a lot of emphasis on macrocyclic peptides as significant cancer therapy agents, mostly due to their decreased toxicity to normal cells and synthetic accessibility. For example, a macrocycle-quinoxalinone class pan-Cdk inhibitor acts as anti-tumor agent [51]. Below are a few examples of synthetic macrocycles used as anti-cancer agents.
5.2.1 Synthetic macrocycle as anti-breast and anti-CNS cancer agents
A new acylated cyclopentapeptide namely, Cyclo-(Nα-dipicolinoyl)-bis-[L-Leu-DL-Nval]-L-Lys OMe (Figure 9) showed early signs of promising cytotoxic action. The molecule exhibited possible anti-proliferative effects, primarily attributed to DNA intercalation, and metal sensor properties, specifically for lead cations (a pollutant) [52].
Figure 9.
Structure of Cyclo-(Nα-dipicolinoyl)-bis-[L-Leu-DL-Nval]-L-Lys OMe acting as an anti-breast and anti-CNS cancer agent.
5.2.2 Synthetic macrocycle as anti-hepatic and anti-breast cancer agents
Novel macrocyclic compounds of pyridoheptapeptides (Figure 10) have been generated. The anticancer potential of these heptapeptidopyridine compounds was assessed in comparison to commonly used cancer-fighting drugs. The antitumor potential of each produced molecule was assessed using two human cancer cell lines, MCF-7 and HepG-2. Both anti-hepatic and anti-breast cancer activities were demonstrated by 1a–c. Only anti-hepatic cancer action has been shown by 2a–c [53].
Figure 10.
Structure of pyridoheptapeptides acting as anti-hepatic and anti-breast cancer agents.
5.2.3 Synthetic macrocylces as anti-leukemia agents
N-(2-aminophenyl) benzamide acridine (Figure 11) demonstrated multi-targeting ability against HDAC (IC50 = 87 nM), transmembrane ligand-activated receptor tyrosine kinase (FLT3) (IC50 = 87 nM), and Janus kinase 2 (IC50 = 686 nM), exhibiting a high lethal effect on human erythroleukemia (HEL) cells and the human acute myeloid leukemia cell line MV4–11. This compound functions by inhibiting Topoisomerase 1 and HDAC, which stops cell proliferation (IC50 0.12–0.35 μM) that is caused by G0/G1 stoppage of the cell cycle [54]. Innovative pyrimidine-based macrocycle SB1518 exhibits a distinct kinase profile with selective inhibition of fms-like tyrosine kinase-3 (FLT3; IC50 = 22 nM) and Janus Kinase-2 (JAK2; IC50 = 23 and 19 nM for JAK2WT and JAK2V617F, respectively) within the JAK family (IC50 = 1280, 520 and 50 nM for JAK1, JK3, and TYK2, respectively). Clinical trials including myelofibrosis and lymphoma patients are also validating this drug [55].
Figure 11.
Structures of N-(2-aminophenyl) benzamide acridine and Pacritinib acting as as anti-leukemia agents.
5.2.4 Synthetic macrocylces as anti-angiogenic agents
A cyclic pentapeptide called cilengitide (Figure 12) is presently being studied in phase II clinical trials for glioblastomas and in phase III trials for a number of different malignancies. This drug targets the integrins αvβ3, αvβ5, and α5β1, making it the first small molecule anti-angiogenic agent [56, 57].
Figure 12.
Structure of Cilengitide as anti-angiogenic agents.
6. Effect of varying ring size and linker functionalization of macrocyclic drug on structure–activity relationships (SARs)
Studies of the structure–activity relationship show that a macrocyclic structure’s inhibitory action is influenced by its ring size and ring functionalities. Table 3 provides a detailed description of the impact of altering a macrocyclic linker, encompassing information on Hsp90 inhibition, cell-growth inhibition, water solubility, and microsomal stability. The first steps in determining the ideal linker length included developing macrocycles with 11–13 atoms that had an amine inside the linker. Various potencies, aqueous solubilities (starting at 100 μg/ml), and metabolic stabilities were noted in relation to the macrocyclic tether’s length, composition, and substitution. Despite the complicated appearance of SARs, potency was found to be sensitive to the degree and chirality of alkyl substitution in the linker, indicating that conformational preferences may change and that affinity within the series may be driven by steric problems. It has been found that the best platform for multiparameter optimization is a 12-membered macrocycle. Interestingly, compounds A, D and G show that as the macrocycle size expanded, the water solubility and rat liver microsome stability of this series dropped. This may possibly be a result of the smaller macrocycle pushing the biaryl system to twist and break planarity, which has been demonstrated to promote solubility, even though it is partially reflecting rising lipophilicity with increasing ring size and substitution [58]. A more planar biaryl system ought to be possible due to the larger macrocycles.
Table 3.
SARs for macrocyclic (A-G) Hsp90 inhibitors and differ in terms of linker functionalization and ring size.
To sum up, macrocyclic compounds show promise as cancer treatment agents. Macrocyclic compounds are being developed for cancer therapy at a rapid pace due to the increasing need for medications to treat cancer. One of the many cancer treatment approaches that is accessible is chemotherapy. Nevertheless, a number of existing chemotherapeutic drugs have significant side effects, such as drug resistance, inefficiency, and intricately linked pathways in the etiology of cancer disorders. It has been suggested that multi-target macrocyclic compounds are an efficient way to treat cancer. Several kinds of synthetic and naturally occurring macrocyclic compounds possessing multi-targeting capabilities have been assessed in this chapter as possible chemotherapeutic treatments for diverse types of cancer. These substances work by inhibiting cell development, causing apoptosis, and reducing cell metastasis, among other effects.
This chapter is intended to serve as a guide for the development of macrocyclic compounds. The structural class of macrocycles offers substantial promise for the development of new drugs. Despite their current lack of exploration, it is expected that in the upcoming years, interest in and success with this class of compounds will increase significantly. More medications based on macrocyclic compounds with particular curative powers will be created in the future.
References
1.Driggers EM, Hale SP, Lee J, Terrett NK. The exploration of macrocycles for drug discovery—An underexploited structural class. Nature Reviews. Drug Discovery. 2008;7:608-624. DOI: 10.1038/nrd2590
2.Wessjohann LA, Ruijter E, Garcia-Rivera D, Brandt W. What can a chemist learn from nature’s macrocycles?–A brief, conceptual view. Molecular Diversity. 2005;9:171-186. DOI: 10.1007/s11030-005-1314-x
3.Mallinson J, Collins I. Macrocycles in new drug discovery. Future Medicinal Chemistry. 2012;4:1409-1438. DOI: 10.4155/fmc.12.93
4.Marti-Centelles V, Pandey MD, Burguete MI, Luis SV. Macrocyclization reactions: The importance of conformational, configurational, and template-induced preorganization. Chemical Reviews. 2015;115:8736-8834. DOI: 10.1021/acs.chemrev.5b00056
5.Dougherty PG, Sahni A, Pei D. Understanding cell penetration of cyclic peptides. Chemical Reviews. 2019;119:10241-10287. DOI: 10.1021/acs.chemrev.9b00008
6.Marsault E, Peterson ML. Macrocycles are great cycles: Applications, opportunities, and challenges of synthetic macrocycles in drug discovery. Journal of Medicinal Chemistry. 2011;54:1961-2004. DOI: 10.1021/jm1012374
7.Fairlie DP, Abbenante G, March DR. Macrocyclic peptidomimetics-forcing peptides into bioactive conformations. Current Medicinal Chemistry. 1995;2:654-686. DOI: 10.2174/0929867302666220218001506
8.Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a Cancer Journal for Clinicians. 2021;71:209-249. DOI: 10.3322/caac.21660
9.Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA: A Cancer Journal for Clinicians. 2021;71:7-33. DOI: 10.3322/caac.21708
10.Dissanayake S, Denny WA, Gamage S, Sarojini V. Recent developments in anticancer drug delivery using cell penetrating and tumor targeting peptides. Journal of Controlled Release. 2017;250:62-76. DOI: 10.1016/j.jconrel.2017.02.006
11.Erb W, Zhu J. From natural product to marketed drug: The tiacumicin odyssey. Natural Product Reports. 2013;30:161-174. DOI: 10.1039/C2NP20080E
12.Surade S, Blundell TL. Structural biology and drug discovery of difficult targets: The limits of ligandability. Chemistry & Biology. 2012;19:42-50. DOI: 10.1016/j.chembiol.2011.12.013
13.DeLorbe JE, Clements JH, Whiddon BB, Martin SF. Thermodynamic and structural effects of macrocyclic constraints in protein− ligand interactions. ACS Medicinal Chemistry Letters. 2010;1:448-452. DOI: 10.1021/ml100142y
14.Garcia Jimenez D, Poongavanam V, Kihlberg J. Macrocycles in drug discovery-learning from the past for the future. Journal of Medicinal Chemistry. 2023;66:5377-5396. DOI: 10.1021/acs.jmedchem.3c00134
15.Mortensen KT, Osberger TJ, King TA, Sore HF, Spring DR. Spring, strategies for the diversity-oriented synthesis of macrocycles. Chemical Reviews. 2019;119:10288-10317. DOI: 10.1021/acs.chemrev.9b00084
16.Farzam K, Nessel TA, Quick J. Erythromycin. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023
17.Navya P, Kaphle A, Srinivas S, Bhargava SK, Rotello VM, Daima HK. Current trends and challenges in cancer management and therapy using designer nanomaterials. Nano Convergence. 2019;6:1-30. DOI: 10.1186/s40580-019-0193-2
18.Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, et al. Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. In: Seminars in Cancer Biology. Elsevier. 2015;35:S25-S54. DOI: 10.1016/j.semcancer.2015.02.006
19.Feyen F, Cachoux F, Gertsch J, Wartmann M, Altmann KH. Epothilones as lead structures for the synthesis-based discovery of new chemotypes for microtubule stabilization. Accounts of Chemical Research. 2008;41:21-31. DOI: 10.1021/ar700157x
20.Nogales E, Grayer Wolf S, Khan IA, Ludueña RF, Downing KH. Structure of tubulin at 6.5 Å and location of the taxol-binding site. Nature. 1995;375:424-427. DOI: 10.1038/375424a0
21.Mani S, Ghalib M, Goel S, Serradell N, Bolos J, Rosa E. Ixabepilone. Drugs of the Future. 2007:32. DOI: 10.1358/dof.2007.032.12.1157611
22.Yang J, Zhu Q, Wu Y, Qu X, Liu H, Jiang B, et al. Utilization of macrocyclic peptides to target protein-protein interactions in cancer. Frontiers in Oncology. 2022;12:992171. DOI: 10.3389/fonc.2022.992171
23.Hanahan D. Hallmarks of cancer: New dimensions. Cancer Discovery. 2022;12:31-46. DOI: 10.1158/2159-8290.CD-21-1059
24.Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS, et al. FDA approval summary: Temsirolimus as treatment for advanced renal cell carcinoma. The Oncologist. 2010;15:428-435. DOI: 10.1634/theoncologist.2009-0178
25.Westin GF, Perez CA, Wang E, Glück S. Biologic impact and clinical implication of mTOR inhibition in metastatic breast cancer. The International Journal of Biological Markers. 2013;28:233-241. DOI: 10.5301/JBM.5000040
26.Chan DL, Segelov E, Singh S. Everolimus in the management of metastatic neuroendocrine tumours. Therapeutic Advances in Gastroenterology. 2017;10:132-141. DOI: 10.1177/1756283X16674660
27.Turner SG, Peters KB, Vredenburgh JJ, Desjardins A, Friedman HS, Reardon DA. Everolimus tablets for patients with subependymal giant cell astrocytoma. Expert Opinion on Pharmacotherapy. 2011;12:2265-2269. DOI: 10.1517/14656566.2011.601742
28.Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. Journal of Clinical Oncology. 2012;30:631-636. DOI: 10.1200/JCO.2011.37.4223
29.Verdaguer H, Morilla I, Urruticoechea A. Eribulin mesylate in breast cancer. Women’s Health. 2013;9:517-526. DOI: 10.2217/WHE.13.61
30.Landhuis E. FDA approves eribulin for advanced liposarcoma. Cancer Discovery. 2016;6:OF1. DOI: 10.1158/2159-8290.CD-NB2016-011
31.Syed YY. Lorlatinib: First global approval. Drugs. 2019;79:93-98. DOI: 10.1007/s40265-018-1041-0
32.Markham A. Lurbinectedin: First approval. Drugs. 2020;80:1345-1353. DOI: 10.1007/s40265-020-01374-0
33.Trigo J, Subbiah V, Besse B, Moreno V, López R, Sala MA, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: A single-arm, open-label, phase 2 basket trial. The Lancet Oncology. 2020;2:645-654. DOI: 10.1016/S1470-2045(20)30068-1
34.Wagner AJ, Ravi V, Riedel RF, Ganjoo K, Van Tine BA, Chugh R, et al. Nab-Sirolimus for patients with malignant perivascular epithelioid cell tumors. Journal of Clinical Oncology. 2021;39:3660-3670. DOI: 10.1200/JCO.21.01728
35.Hart S, Goh K, Novotny-Diermayr V, Tan Y, Madan B, Amalini C, et al. Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. Blood Cancer Journal. 2011;1:e44-e44. DOI: 10.1038/bcj.2011.43
36.Song X, Wu Y, Qu X, Jiang B. Applications of macrocyclic molecules in cancer therapy: Target cancer development or overcome drug resistance. MedComm–Oncology. 2023;2:e50. DOI: 10.1002/mog2.50
37.Cui JJ, Rogers E, Zhai D, Deng W, Ung J, Nguyen V, et al. TPX-0131: A next generation macrocyclic ALK inhibitor that overcomes ALK resistant mutations refractory to current approved ALK inhibitors. Cancer Research. 2020;80:5226-5226. DOI: 10.1158/1538-7445.AM2020-5226
38.Amewu RK, Sakyi PO, Osei-Safo D, Addae-Mensah I. Synthetic and naturally occurring heterocyclic anticancer compounds with multiple biological targets. Molecules. 2021;26:134. DOI: 10.3390/molecules26237134
39.Yuan H, Ma Q, Ye L, Piao G. The traditional medicine and modern medicine from natural products. Molecules. 2016;21:559. DOI: 10.3390/molecules21050559
40.Newman DJ, Cragg GM, Snader KM. Natural products as sources of new drugs over the period 1981−2002. Journal of Natural Products. 2003;66:1022-1037. DOI: 10.1021/np030096l
41.Li-Weber M. New therapeutic aspects of flavones: The anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treatment Review. 2009;35:57-68. DOI: 10.1016/j.ctrv.2008.09.005
42.Crampton SL, Adams EG, Kuentzel SL, Li LH, Badiner G, Bhuyan BK. Biochemical and cellular effects of didemnins A and B. Cancer Research. 1984;44:1796-1801
43.Chun HG, Davies B, Hoth D, Suffness M, Plowman J, Flora K, et al. Didemnin B: The first marine compound entering clinical trials as an antineoplastic agent. Investigational New Drugs. 1986;4:279-284. DOI: 10.1007/BF00179597
44.Ahuja D, Vera MD, SirDeshpande BV, Morimoto H, Williams PG, Joullié MM, et al. Inhibition of protein synthesis by didemnin B: How EF-1α mediates inhibition of translocation. Biochemistry. 2000;39:4339-4346. DOI: 10.1021/bi992202h
45.Li LH, Timmins LG, Wallace TL, Krueger WC, Prairie MD, Im WB. Mechanism of action of didemnin B, a depsipeptide from the sea. Cancer Letters. 1984;23:279-288. DOI: 10.1016/0304-3835(84)90095-8
46.Bewley CA, Debitus C, Faulkner D. Microsclerodermins A and B. Antifungal cyclic peptides from the lithistid sponge Microscleroderma sp. Journal of the American Chemical Society. 1994;116:7631-7636. DOI: 10.1021/ja00096a020
47.Guzmán EA, Maers K, Roberts J, Kemami-Wangun HV, Harmody D, Wright AE. The marine natural product microsclerodermin A is a novel inhibitor of the nuclear factor kappa B and induces apoptosis in pancreatic cancer cells. Investigational New Drugs. 2015;33:86-94. DOI: 10.1007/s10637-014-0185-3
48.Shin Y, Kim GD, J-e J, Shin J, Lee SK. Antimetastatic effect of halichondramide, a trisoxazole macrolide from the marine sponge Chondrosia corticata, on human prostate cancer cells via modulation of epithelial-to-mesenchymal transition. Marine Drugs. 2013;11:2472-2485. DOI: 10.3390/md11072472
49.Trisciuoglio D, Uranchimeg B, Cardellina JH, Meragelman TL, Matsunaga S, Fusetani N, et al. Induction of apoptosis in human cancer cells by candidaspongiolide, a novel sponge polyketide. Journal of the National Cancer Institute. 2008;100:1233-1246. DOI: 10.1093/jnci/djn239
50.Whitson EL, Pluchino KM, Hall MD, McMahon JB, McKee TC. New candidaspongiolides, tedanolide analogues that selectively inhibit melanoma cell growth. Organic Letters. 2011;13:3518-3521. DOI: 10.1021/ol201329p
51.Hirai H, Takahashi-Suziki I, Shimomura T, Fukasawa K, Machida T, Takaki T, et al. Potent anti-tumor activity of a macrocycle-quinoxalinone class pan-Cdk inhibitor in vitro and in vivo. Investigational New Drugs. 2011;29:534-543. DOI: 10.1007/s10637-009-9384-8
52.Abo-Ghalia M, Amr A. Synthesis and investigation of a new cyclo (N α-dipicolinoyl) pentapeptide of a breast and CNS cytotoxic activity and an ionophoric specificity. Amino Acids. 2004;26:283-289. DOI: 10.1007/s00726-003-0042-8
54.Ning C-Q, Lu C, Hu L, Bi Y-J, Yao L, He Y-J, et al. Macrocyclic compounds as anti-cancer agents: Design and synthesis of multi-acting inhibitors against HDAC, FLT3 and JAK2. European Journal of Medicinal Chemistry. 2015;95:104-115. DOI: 10.1016/j.ejmech.2015.03.034
55.Hart S, Goh K, Novotny-Diermayr V, Hu C, Hentze H, Tan Y, et al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia. 2011;25:1751-1759. DOI: 10.1038/leu.2011.148
56.Mas-Moruno C, Rechenmacher F, Kessler H. Cilengitide: The first anti-angiogenic small molecule drug candidate. Design, synthesis and clinical evaluation. Anti-Cancer Agents in Medicinal Chemistry. 2010;10:753-768. DOI: 10.2174/187152010794728639
57.Stupp R, Van Den Bentm G, et al. Cilengitide in newly diagnosed glioblastoma with MGMT promoter methylation: Protocol of a multicenter, randomized, open-label, controlled phase III trial (CENTRIC). Journal of Clinical Oncology. 2010;28:TPS152-TPS152. DOI: 10.1200/jco.2010.28.15_suppl.tps15
58.Ishikawa M, Hashimoto Y. Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. Journal of Medicinal Chemistry. 2011;54:1539-1554. DOI: 10.1021/jm101356p
Written By
Sadia Rani, Samina Aslam, Ali Irfan, Emilio Mateev, Sami A. Al-Hussain and Magdi E.A. Zaki
Submitted: 06 February 2024Reviewed: 13 February 2024Published: 13 May 2024
Open access peer-reviewed chapter - ONLINE FIRST
