Design and synthesis of benzo[c,d]indolone-pyrrolobenzodiazepine conjugates as potential anticancer agents

Kamal, Ähmed; Ramakrishna, G.; Nayak, V. Lakshma; Raju, P. V. K.; Rao, A. V. Subba; Arutla, Viswanath; Vishnuvardhan, M.V.P.S.; Sistla, Ramakrishna; Srinivas, G.

doi:10.1016/j.bmc.2011.12.003

Cited by 53 publications

(22 citation statements)

References 37 publications

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“…A mixture of 50 ml of 2X assay buffer, 50 ml cell lysate and 2 ml of caspase-3 substrate was taken in a 96-well black polystyrene plate. The reaction was allowed to take place for 1 h. The fluorescence generated by the release of the fluorogenic group AFC after cleavage by caspase-3 was measured by excitation at 400 nm and emission at 505 nm for every 5 min over a period of 1 h. Protein content was estimated by Bradford's method and was normalized [24].…”

Section: Caspase-3mentioning

confidence: 99%

Synthesis and anticancer activity of novel fused pyrimidine hybrids of myrrhanone C, a bicyclic triterpene of Commiphora mukul gum resin

et al. 2015

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Myrrhanone C [8(R)-3-oxo-8-hydroxypolypoda-13E,17E,21-triene], a bicyclic triterpene isolated from the gum resin of Commiphora mukul, has been chemically transformed to synthesize a series of ten novel pyrimidine hybrids in good to excellent yields. The synthesized compounds (2-22) were evaluated for their anticancer potential against a panel of six cancer cell lines, namely A-549 (lung), Hela (cervical), MCF-7 (breast), ACHN (renal), Colo-205 (colon) and B-16 (mouse melanoma) by employing the MTT assay. In general, the synthesized compounds showed significant anticancer activity against all the cancer cell lines tested. Interestingly, the pyrimidine hybrids 18 and 19 showed good activity against the A-549, MCF-7, B-16, Colo-205 and ACHN cancer cell lines with [Formula: see text] values between 7.7-37.8 [Formula: see text]M. Most significantly, compounds 19 (IC[Formula: see text]: 7.7 [Formula: see text]M) and 18 (IC[Formula: see text]: 9.5 [Formula: see text]M) showed about five- and six-fold enhanced activities, respectively, compared to the parent myrrhanone C (1) against A-549 cell line. Flow cytometric analysis revealed that compounds 18 and 19 induced apoptosis in A-549 cells and arrested the cell growth in the G0/G1 phase.

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Section: Caspase-3mentioning

confidence: 99%

Synthesis and anticancer activity of novel fused pyrimidine hybrids of myrrhanone C, a bicyclic triterpene of Commiphora mukul gum resin

et al. 2015

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“…After that, DNA laddering was determined by 2 % agarose gel electrophoresis. [59] Protein extraction and Western blot analysis A549 cells were treated with compound 11 x (0.5 and 1 mm) for 48 h. Cells were lysed in ice-cold radioimmunoprecipitation assay (RIPA) buffer (1 PBS, 1 % NP-40 detergent, 0.5 % sodium deoxycholate, and 0.1 % SDS) containing phenylmethanesulfonyl fluoride (PMSF) (100 mg mL À1 ), aprotinin (5 mg mL…”

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confidence: 99%

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

et al. 2014

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A series of chalcone conjugates featuring the imidazo[2,1-b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF-7, A549, HeLa, DU-145 and HT-29). These new hybrid molecules have shown promising cytotoxic activity with IC50 values ranging from 0.64 to 30.9 μM. Among them, (E)-3-(6-(4-fluorophenyl)-2,3-bis(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)-1-(pyridin-2-yl)prop-2-en-1-one (11 x) showed potent antiproliferative activity with IC50 values ranging from 0.64 to 1.44 μM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate (11 x) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell-cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase-3, DNA fragmentation analysis, and Annexin V-FITC assay. Moreover, molecular docking studies indicated that this conjugate (11 x) interacts and binds efficiently with the tubulin protein.

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“…2 was prepared based on the adoption of method by Kamal et al ( 2012 ). Napthalic anhydride (1.98 g, 10 mmol), hydroxylamine hydrochloride (0.69 mg, 10 mmol), and dry pyridine (5 ml) were added to dried three-necked flask.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Dihydrobenzo[cd]indole-6-sulfonamide as TNF-α Inhibitors

et al. 2018

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Tumor necrosis factor-α (TNF-α) plays a pivotal role in inflammatory response. Dysregulation of TNF can lead to a variety of disastrous pathological effects, including auto-inflammatory diseases. Antibodies that directly targeting TNF-α have been proven effective in suppressing symptoms of these disorders. Compared to protein drugs, small molecule drugs are normally orally available and less expensive. Till now, peptide and small molecule TNF-α inhibitors are still in the early stage of development, and much more efforts should be made. In a previously study, we reported a TNF-α inhibitor, EJMC-1 with modest activity. Here, we optimized this compound by shape screen and rational design. In the first round, we screened commercial compound library for EJMC-1 analogs based on shape similarity. Out of the 68 compounds tested, 20 compounds showed better binding affinity than EJMC-1 in the SPR competitive binding assay. These 20 compounds were tested in cell assay and the most potent compound was 2-oxo-N-phenyl-1,2-dihydrobenzo[cd]indole-6-sulfonamide (S10) with an IC50 of 14 μM, which was 2.2-fold stronger than EJMC-1. Based on the docking analysis of S10 and EJMC-1 binding with TNF-α, in the second round, we designed S10 analogs, purchased seven of them, and synthesized seven new compounds. The best compound, 4e showed an IC50-value of 3 μM in cell assay, which was 14-fold stronger than EJMC-1. 4e was among the most potent TNF-α organic compound inhibitors reported so far. Our study demonstrated that 2-oxo-N-phenyl-1,2-dihydrobenzo[cd]indole-6-sulfonamide analogs could be developed as potent TNF-α inhibitors. 4e can be further optimized for its activity and properties. Our study provides insights into designing small molecule inhibitors directly targeting TNF-α and for protein–protein interaction inhibitor design.

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Design and synthesis of benzo[c,d]indolone-pyrrolobenzodiazepine conjugates as potential anticancer agents

Cited by 53 publications

References 37 publications

Synthesis and anticancer activity of novel fused pyrimidine hybrids of myrrhanone C, a bicyclic triterpene of Commiphora mukul gum resin

Synthesis and anticancer activity of novel fused pyrimidine hybrids of myrrhanone C, a bicyclic triterpene of Commiphora mukul gum resin

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

Design, Synthesis, and Evaluation of Dihydrobenzo[cd]indole-6-sulfonamide as TNF-α Inhibitors

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