Optimization of peptide coupling reaction (
Abstract
A highly efficient protocol was developed for the synthesis of 3-(indoline-1-carbonyl)-N-(substituted) benzene sulfonamide analogs with excellent yields. The new 3-(indoline-1-carbonyl)-N-(substituted) benzene sulfonamide derivatives (4a-g and 5a-g) were evaluated in vitro anticancer activity against a series of different cell lines like A549 (lung cancer cell), HeLa (cervical), MCF-7 (breast cancer cell) and Du-145 (prostate cancer cell) respectively. The results of the anticancer activity data revealed that most of the tested compounds showed IC50 values from 1.98 to 9.12 μM in different cell lines. Compounds 4b, 4d, 5d, and 5g were the most potent, with IC50 values ranging from 1.98 to 2.72 μM in different cell lines.
Keywords
- indoline
- sulfonamide
- anticancer
1. Introduction
Antibiotic resistant bacteria are rapidly emerging worldwide [1]. The various biological active heterocyclic compounds, the indole derivatives are the key structural feature commonly found in natural products [2, 3] and bioactive molecules, such as tryptophan [4], tryptamine [5], and auxin [6]. Furthermore, it has been reported that sharing of the indole 3-carbon in the formation of spiroindoline derivatives highly enhances biological activity [7]. Moreover, some of the compounds containing benzenesulfonamide moiety also show broad spectrum biological properties such as elastase inhibitors [8], carbonic anhydrase inhibitors [9], clostridium histolyticum collogenase inhibitors [10] as well as herbicides and plant growth regulators [11]. Sulfonamides are common motifs in many drugs and medicinal compounds and play an important role in their bioactivity since the development of sulfa antibiotics in the 1930s [12]. Common drugs such as glibenclamide [13], sultiame [14], and COX-II inhibitors Piroxicam [15], Ampiroxicam [16], and Celecoxib [17] containing a sulfonyl moiety, which displays potential activity across a variety of biological targets. The sulfonamides are organic sulfur compounds which have attracted the attention for their better pharmacological activity [18, 19, 20]. It is interesting to note that the sulfonamide containing moiety is known to have some biological and pharmaceutical properties, such as, antitumor, antibacterial, thrombin inhibition, and antifungal activities [21, 22, 23].
In view of the above considerations, in continuation of our previous work on triazoles, pyrimidine, thiazoles and thiazolidinones of pharmaceutical interest [24, 25, 26, 27, 28, 29, 30] we report here on the synthesis and anticancer activity of new 3-(indoline-1-carbonyl)-N-(substituted) benzene sulfonamide analogs.
2. Results and discussion
2.1 Chemistry
The aim of this work was to design and synthesize a novel series of benzenesulfonamide incorporating biologically active indoline moieties to evaluate their anticancer activity. We have synthesized new derivatives containing sulfonamide linkage in frame work. The synthetic methods adopted for the preparation of the N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide derivatives (
Sr. no. | Coupling reagent | Base | Solvent | Time (h) | Yield (%) |
---|---|---|---|---|---|
1. | HATU (1.1 equiv.) | TEA (1.2 equiv.) | DMF | 14 | 57 |
2. | HATU (1.1 equiv.) | DIPEA (1.2 equiv.) | DMF | 14 | 55 |
3. | PyBOP (1.1 equiv.) | TEA (1.2 equiv.) | THF | 14 | 45 |
4. | PyBOP (1.1 equiv.) | DIPEA (1.2 equiv.) | THF | 14 | 50 |
5. | EDCI (1.5 equiv.) | TEA (2.5 equiv.) | DMF | 14 | 62 |
HOBt (1.5 equiv.) | |||||
6. | EDCI (1.5 equiv.) | DIPEA (2.5 equiv.) | DMF | 14 | 72 |
HOBt (1.5 equiv.) | |||||
7. | EDCI (1.5 equiv.) | TEA (4 equiv.) | DMF | 14 | 78 |
8. | HOBt (1.5 equiv.) | DIPEA (4 equiv.) | DMF | 14 | 67 |
9. | T3P (1.2 equiv.) | TEA (2.5 equiv.) | DCM | 10 | 50 |
10. | T3P (1.2 equiv.) | DIPEA (2.5 equiv.) | DCM | 10 | 60 |
11. | EDCI (1.5 equiv.) | DIPEA (2.5 equiv.) | DCM | 10 | 95 |
Acid (1 equiv.) and indoline (1.2 equiv.) |
For synthesis of compound
For the synthesis of compounds from
For synthesis of
For synthesis of
2.2 Biological evaluation: anticancer activity
The synthesized compounds were evaluated for their
5-Flourouracil is used for anal, breast, colorectal, esophageal, stomach, pancreatic and skin cancers mainly. The response parameter calculated was the IC50 value, which corresponds to the concentration required for 50% inhibition of cell viability. The results are presented in Table 2, where all compounds exhibit moderate to good activity compared to 5-fluorouracil as positive control. In the case of the human lung cancer cell line (A549) compounds
Compound | A549 (lung cancer cell) | HeLa (cervical cancer cell) | MCF-7 (breast cancer cell) | Du-145 (prostate cancer cell) |
---|---|---|---|---|
4a | 1.98 ± 0.12 | 3.83 ± 0.16 | 3.52 ± 0.06 | 3.86 ± 0.16 |
4b | 2.81 ± 0.13 | 2.92 ± 0.08 | 2.32 ± 0.22 | 3.82 ± 0.12 |
4c | 4.81 ± 0.12 | 6.32 ± 0.04 | 4.32 ± 0.06 | 3.73 ± 0.12 |
4d | 2.82 ± 0.11 | 1.99 ± 0.22 | 2.36 ± 0.12 | 3.52 ± 0.11 |
4e | 3.86 ± 0.08 | 4.38 ± 0.06 | 3.63 ± 0.12 | 6.52 ± 0.22 |
4f | 2.72 ± 0.11 | 3.87 ± 0.08 | 4.12 ± 0.06 | 3.86 ± 0.22 |
4g | 3.14 ± 0.14 | 3.98 ± 0.12 | 4.86 ± 0.11 | 4.57 ± 0.11 |
5a | 8.48 ± 0.14 | 9.12 ± 0.08 | 7.82 ± 0.08 | 9.12 ± 0.06 |
5b | 3.82 ± 0.08 | 4.13 ± 0.12 | 3.13 ± 0.11 | 3.52 ± 0.08 |
5c | 4.13 ± 0.12 | 5.16 ± 0.08 | 6.12 ± 0.12 | 4.52 ± 0.11 |
5d | 2.06 ± 0.12 | 2.12 ± 0.08 | 2.52 ± 0.16 | 5.12 ± 0.08 |
5e | 2.52 ± 0.11 | 3.52 ± 0.11 | 4.48 ± 0.08 | 4.08 ± 0.11 |
5f | 4.48 ± 0.08 | 4.98 ± 0.11 | 5.17 ± 0.22 | 5.18 ± 0.18 |
5g | 2.73 ± 0.08 | 2.12 ± 0.12 | 2.12 ± 0.08 | 2.12 ± 0.04 |
5-FU | 1.61 ± 0.12 | 1.72 ± 0.18 | 1.81 ± 0.10 | 1.89 ± 0.12 |
2.3 General experimental procedure for the synthesis of N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (5a-g)
2.3.1 Step-1: preparation of ethyl 3-(chlorosulfonyl)benzoate (2)
To a stirred solution of ethyl benzoate (10 g, 67 mmol) in DCM (25 mL). RM was cooled to 0°C and chloro sulfonic acid (9 g, 73 mmol) was added drop wise and stirred for 1 h at same temperature followed by stirring at room temperature for 1 h. After completion of reaction, evaporate reaction mixture under reduced pressure and obtained gummy material is washed with excess of hexane and it is crystalized from 20% ethyl acetate: hexane mixture to obtain white solid as ethyl 3-(chlorosulfonyl)benzoate
2.3.2 Step-2: preparation of ethyl 3-(N-(o-tolyl)sulfamoyl)benzoate (3a-g)
To a stirred solution of ethyl 3-(chlorosulfonyl)benzoate
2.3.3 Step-3: preparation of 3-(N-(o-tolyl)sulfamoyl)benzoic acid (4a-g)
To a stirred solution of ethyl 3-(N-(o-tolyl)sulfamoyl)benzoate (
2.3.4 Step-4: N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (5a-g)
The compound 3-(N-(o-tolyl)sulfamoyl)benzoic acid
3. Conclusion
An effective method was developed which provided an easy access to a new series N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (
Acknowledgments
The authors are thankful to the Head, Department of Chemistry, Deogiri college, Aurangabad for the laboratory facility.
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