Common anticancer drugs along with their mechanisms of action.
Abstract
Cancer is one of the major life burdens and around 18.1 million new cancer cases and 9.6 million deaths have been estimated in 2018 globally. Recent reports of the World Health Organization (WHO) stated that about one in six death cases globally is mainly due to cancer. Hence, the development of efficacious drugs with novel mechanisms is necessary for various cancer types. The chemotherapy drug resistance and non-selectivity toward targets have turned the current cancer research on to the highly emerging selective targets for the development of potential anticancer agents. Benzimidazole is regarded as an essential pharmacophore of the cancer research because of wide anticancer potentials with versatile mechanisms to inhibit the tumor progression and also facile synthetic strategies for an easy synthesis of various benzimidazole derivatives. The selective anticancer potentials also depend on the substitution of the benzimidazole nucleus. Therefore, it would lead to providing a path for the development of novel target-specific and highly effective benzimidazole-based anticancer agents.
Keywords
- benzimidazole
- cancer
- specific targets
- synthetic strategies
1. Introduction to cancer
Cancer is one of the dreadful diseases in the world and mainly characterized by uncontrolled cell proliferation. Worldwide, one in six women and one in five men develop cancer during their lifetime, and one in eleven women and one in eight men die from the disease. Global data clearly show that nearly half of the new cases and more than half of the cancer deaths worldwide in 2018 are estimated to occur in Asian countries because the region has nearly 60% of the global population and it is estimated to have a rise of over 21.4 million new cases per year, with 13.2 million cancer deaths, by 2030. The top three cancer types
Radiotherapy, surgery, and chemotherapy are the usual cancer treatment strategies [5]. Among these, chemotherapy is considered as one of the efficient and first-line strategies in suppressing tumor prognosis and eradication. Most of the chemotherapeutic drugs target the key cellular mechanisms and inhibit the cell division and thereby prevent cancer cell multiplication. Current clinical anticancer drugs usually act on metabolically effective or fast replicating cells and show drawbacks such as poor selectivity between cancer cells and healthy cells [6]. Cancer cells generally disturb the cell signaling pathways and tissue morphogenesis for the neoplastic propagation of tumors. Therefore, targeting these cell pathways by cytotoxic agents has been a proven therapeutic approach to subside tumor growth and disease progression. Unfortunately, most of the cytotoxic drugs cause side effects due to the poor selectivity and specificity toward cancer cells. However, the higher toxic profiles and poor tolerance of the present chemotherapeutic drugs are major obstacles to the effective treatment of cancer [7, 8]. Therefore, it is highly pertinent to design and synthesize new anticancer agents with improved efficiency and reduced side effects to complement the present chemotherapeutic approaches. Identifying new drugs and drug combinations for cancer treatment is essential to combat this lethal disease. Hence, further research that emphasizes mainly on the development of efficient chemotherapeutic agents is an emerging area of research in the field of medicinal chemistry. The list of various available chemotherapeutic agents has been shown in Table 1 [9].
Alkylating agents | Alkylation of DNA bases Procarbazine, dacarbazine, and temozolomide |
---|---|
DNA cleaving agents | Cause strand scission at the binding site-Bleomycin |
Cross-linking agents | Binding to DNA results in intra- and inter-strand cross-linking Platinum complexes-carboplatin, cisplatin, oxaliplatin Nitrogen mustards-cyclophosphamide, ifosfamide |
Intercalating agents | Stacking between DNA base pairs Anthracyclines-doxorubicin, epirubicin Mitoxantrone and actinomycin-D |
Topoisomerase inhibitors | Topoisomerase I-camptothecins Topoisomerase II-Anthracyclines, etoposide |
Purine analogues | Mercaptopurine |
Pyrimidine analogues | 5-Fluorouracil |
DHFR inhibitors | Methotrexate |
Taxol | Paclitaxel, Docetaxel |
Vinca alkaloids | Vincristine, Vinblastine, Vinorelbine |
Small molecule | Imatinib (Gleevec): inhibits ABL, c-Kit kinase, PDGFR Gefitinib (Iressa): inhibits EGFR |
Monoclonal antibody | Trastuzumab: inhibits EGFR2, HER2 |
Monoclonal antibody | Bevacizumab (Avastin): targets VEGF |
2. Introduction to Benzimidazole
Benzimidazole heterocyclic nucleus can be termed as “Master Key” due to its overwhelming biological profile and synthetic applications in medicinal chemistry. It is among the top five most common five-membered aromatic nitrogen heterocycles in U.S. FDA-approved pharmaceutical drugs [10]. Benzimidazoles are structural isosteres of nucleobases due to the fused nitrogen nuclei and they readily interact with biomolecular targets and elicit many biological activities such as anticancer [11], anti-inflammatory [12], antiulcer [13], anti-hypertensive [14], and anthelmintic [15]. Akhtar et al. in his recent review described the therapeutic evolution of benzimidazole scaffolds during the last quinquennial period [16]. This nitrogen-containing heterocycle was present in a number of well-established clinical drugs with diverse therapeutic activities. For instance, drugs like rabeprazole (
In 1954, Tamm, Folkers, and co-workers first reported the synthesis and antiviral activities of halogenated benzimidazole nucleosides [22]. They found that 5,6-dichloro-1-β-D-ribofuranosyl benzimidazole (DRB) has multiple biological activities including activity against RNA and DNA viruses. DRB inhibits cellular RNA polymerase II, thus affecting the multiple cellular processes so that it is more cytotoxic than antiviral. Slayden et al. found that albendazole (
Benzimidazoles have revolutionized the drug discovery process by their diverse range of biological activities, which make this scaffold an indispensable anchor for the innovation of novel therapeutic agents. Thus, the therapeutic potential of the benzimidazole and related drugs has attracted researchers to design and synthesize more potent derivatives with a wide range of pharmacological activities. Owing to the immense synthetic value and extended bioactivities exhibited by benzimidazoles and their derivatives, efforts have been made from time to time to create libraries of these compounds.
3. Target-based benzimidazole derivatives
3.1 Galectin-1 inhibitors
Galectin-1 (Gal-1) is expressed in various normal and pathological conditions and has multiple functions with a wide range of biological activity. Gal-1, a human homodimeric lectin protein of 14KDa, is implicated in many signaling pathways, immune responses associated with cancer progression, neurological conditions, and immune disorders [25]. Gal-1 has a carbohydrate recognition domain (CRD), which is selective toward β-galactosides in the body. Inhibition of human Gal-1 has been regarded as one of the potential therapeutic approaches for the treatment of cancer, as it plays a major role in tumor development and metastasis by modulating various biological functions viz. angiogenesis, apoptosis, migration, and cell immune escape [26]. The overexpression of Gal-1 has been reported in many cancer types like the brain, breast, osteosarcoma, lung, prostate, melanoma, etc. [27]. Gal-1 can mediate neoplastic transformation by interacting with oncogenes, such as H-Ras and promote Ras-mediated signal transduction involving RAF1 and extracellular signal-regulated kinase (ERK). Gal-1 multivalently mediates tumor cell-ECM adhesion at the primary site by cross-linking cell surface glycoproteins, such as integrins, and glycosylated proteins in the ECM, such as laminin and fibronectin [28]. Hence, Gal-1 is regarded as a promising molecular target for the development of new therapeutic drugs for cancer.
Recently, a new series of 1-benzyl-1H-benzimidazole derivatives have been synthesized as Gal-1-mediated anticancer agents. The target compound (
Tsung-Chieh Shih et al. reported a novel Gal-1 inhibitor named LLS2 (
The same group recently published a more potent Gal-1 inhibitor LLS3 (
3.2 Tubulin protein inhibitors
Tubulin is one of the members of a small family of globular proteins. Several isoforms are present out of which α- and β-tubulins are the most common members of tubulin. The cellular protein tubulin is an important protein for replication. Microtubules are hallowing filaments and composed of head and tail polar fashion arrangements of α- and β-tubulins as the constituent subunits. Microtubules contain 13 active protofilaments aligned parallel with the whole axis of the microtubule cylinder. This may provide continuous transport of cellular materials by motor proteins (dynein and kinesin) over distant places. Microtubules also form an integral part of the cytoskeleton and are responsible for the maintenance of cell shape, and motility and intracellular transport of the vesicles, mitochondria, and other components [33, 34]. Moreover, cell division involves the duplication of DNA and the segregation of the replicated chromosomes into two daughter nuclei. The segregation of these chromosomes is mitotic phase is brought by the microtubules. In the formation of the microtubule, the plus (+) end is terminated by β-tubulin whereas the minus (−) end is terminated by α-tubulin. They are always either in a state of polymerization or depolymerization. Microtubules have the ability to shorten or lengthen in a scholastic fashion through loss or addition of α/β-tubulin heterodimers from ends of microtubules. This property is referred to as “dynamic instability” [35, 36]. Microtubules are blessed with a property to grow continuously as long as the free tubulin amount is above a critical level. The critical concentration at the minus end is somewhat higher than at the plus end and the minus end tends to stop growing first. Even above the critical tubulin concentration, its end may suddenly stop growing and begin to shrink. The change from growth to shrinkage has been termed as “catastrophe.” After some time, a shrinking microtubule end may “pause” and/or begin to grow again; the latter process is known as “rescue.” During mitotic cell division, the chromosomes are segregated by the mitotic spindle, which is formed from tubulin microtubules. Therefore, tubulin dynamics have a distinct role in cell division. Some of the drugs affect the microtubulin dynamics and thus cause either polymerization or depolymerization and thereby alter cellular replication. So at the mechanistic level, tubulin is one of the most attractive and challenging approaches for designing new anticancer compounds.
Zhang et al. have synthesized a series of 1,2-diarylbenzimidazole derivatives and reported as potential anticancer agents. Among all, the target molecule (
Miao et al. reported a novel series of 2-aryl-benzimidazole-based dehydroabietic acid derivatives as potential cytotoxic agents via targeting tubulin polymerization. The synthesized molecules were characterized by elemental and analytical techniques. The target compound (
Wang et al. reported a new series of benzimidazole containing benzsulfamide-pyrazole ring derivatives as potential tubulin polymerization inhibitors. The target compound (
Baig et al. have reported a series of imidazo [2,1-b] thiazole-benzimidazole derivatives as antiproliferative agents via tubulin polymerization inhibition. The target molecule (
3.3 Carbonic anhydrase inhibitors
The human carbonic anhydrases (hCAs) are an α-family of carbonic anhydrases class and exist in 16 different isoforms [41]. Based on their location in the body, they are classified into cytosolic hCAs such as CA I, CA II, CA III, CA VII, and CA XIII; transmembrane hCAs such as CA IV, CA IX, CA XII, CA XIV, and CA XV; mitochondrial-bound hCAs such as CA Va and Vb; secretory hCAs such as CA VI; and catalytically inactive isoforms like CA VIII, CA X, and CA XI, which are considered as CA-related proteins (CARPs) [42]. Among all, the hCA isoforms IX and XII are overexpressed in many of cancer types as these are tumor-associated transmembrane bound enzymes, mainly hypoxic tumors, which are regarded as emerging potential targets for various tumor types [43]. The overexpression of hCA isoforms IX and XII further contributes to the tumor progression, angiogenesis, metastasis, and proliferation of a variety of tumor cells [44]. In order to exhibit potential cytotoxicity without adverse effects, an anticancer agent should selectively inhibit tumor-associated hCAs IX and XII over other hCAs. Therefore, current cancer research focuses on the development of various heterocycles that selectively target tumor-linked hCA isoforms IX and XII for effective treatment strategies in cancer therapy [45]. Another hCA isoform II is also found to overexpress in some forms of cancer and other conditions like edema, glaucoma, and epilepsy.
Recently, a new series of 2-substituted-benzimidazole-6-sulfonamides have been reported as anticancer potentials by testing against four physiologically relevant hCAs such as CA I, CA II, CA IX, and CA XII. The analysis of hCA inhibition results showed that the new series of benzimidazole-based sulfonamide derivatives exhibited selective inhibition toward tumor-associated isoforms such as CA IX and CA XII. The target molecule (
3.4 Epidermal growth factor receptor (EGFR) inhibitors
The Epidermal Growth Factor Receptor is a subfamily transmembrane glycoprotein (ErbB-1) of ErbB class of tyrosine kinase receptors and, other subfamilies include HER2/neu (ErbB-2), Her 3 (ErbB-3) and, Her 4 (ErbB-4) [48]. The internal ligands like EGF and TGF𝛼 facilitate the growth-promoting signal to cells by interacting with EGFR receptors and regulate epithelial tissue development and homeostasis [49, 50]. In cancer, especially epithelial malignancies, due to overproduction of EGFR ligands in the tumor micro environment causes continual activation (or) mutations of EGFR receptors, result in enhances epithelial tumor growth, metastasis and invasion [51, 52].
In a recent study, a new series of benzimidazole-based triazole and thiadiazole derivatives were synthesized and evaluated as selective EGFR inhibitors. The single-crystal X-ray crystallographic analysis has been performed to confirm the molecular structure of the target compound. The synthesized compounds were evaluated for their EGFR kinase inhibitory potencies with erlotinib as the reference standard and, most of the compounds showed promising activities. The cell inhibition studies were also performed and the target compound (
Akhtar et al. have synthesized benzimidazole-based pyrazole derivatives through a one-pot multicomponent reaction and evaluated them for their potential anticancer activities. The synthesized compounds were screened against selected human cancer cell lines such as MCF-7, MDA-MB231, A549, HepG2, and HaCaT. The evaluation of EGFR inhibitory activities was performed for all the synthesized compounds. The target compound (
4. Miscellaneous agents
Wu et al. synthesized a series of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives and two representative compounds (
5. Synthetic strategies
The first benzimidazole (2,5-dimethylbenzimidazole) (
Synthesis of benzimidazoles in the presence of various catalysts involves the condensation of
The benzimidazole derivatives (
Hanan et al. have reported one-pot conversion of aromatic and heteroaromatic 2-nitroamines (
6. Conclusion
There are numerous benzimidazole derivatives for various cancer types involving unique types of mechanism. Although it is a widely used pharmacophore, still very few target-specific benzimidazoles are available. Therefore, researchers across the world need to develop new benzimidazole derivatives that are more target specific and help in the cancer treatment to overcome non-selective toxicity and adverse effects. This chapter mainly focused on target-based benzimidazole derivatives and synthetic strategies. Hence, it would give more ideas to young medicinal researchers to develop target-specific benzimidazole derivatives as potential cytotoxic agents.
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