S.N.C.V.L. Pushpavalli

Synthesis and anticancer activity of chalcone-pyrrolobenzodiazepine conjugates linked via 1,2,3-triazole ring side-armed with alkane spacers

Aiming to develop multitarget drugs for the anticancer treatment, a new class of chalcone-pyrrolo[2,1-c] [1,4]benzodiazepine (PBD) conjugates linked through a 1,2,3-triazole moiety containing alkane spacers has been designed and synthesized. Combining these two core pharmacophore structures with modifications at A-C8/C-C2-position of PBD ring system yielded analogs with improved efficacy and have shown promising in vitro anticancer activity ranging from <0.1-2.92 μM. These PBD-conjugates caused G1 cell cycle arrest with effect on G1 cell cycle regulatory proteins such as Cyclin D1 and Cdk4. These conjugates also exhibited inhibitory effect on NF-kB, Bcl-XL proteins that play a vital role in breast cancer cell proliferation. These findings suggest that one of the compound 4d among this series is most effective and has potential for detailed investigations.

Synthesis and biological evaluation of 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydroquinazolinone hybrids as anticancer agents

A series of new 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydro quinazolinone hybrids with different linker architectures have been designed and synthesized. These compounds have been evaluated for their anticancer activity. One of the compounds 4c amongst this series has shown promising anticancer activity. Further some detailed biological assays relating to the cell cycle aspects and tubulin depolymerization activity have been examined with a view to understand the mechanism of action of this conjugate.

Synthesis, DNA-binding ability and anticancer activity of benzothiazole/benzoxazole-pyrrolo[2,1-c][1,4]benzodiazepine conjugates

A series of benzothiazole and benzoxazole linked pyrrolobenzodiazepine conjugates attached through different alkane or alkylamide spacers was prepared. Their anticancer activity, DNA thermal denaturation studies, restriction endonuclease digestion assay and flow cytometric analysis in human melanoma cell line (A375) were investigated. One of the compounds of the series 17d showed significant anticancer activity with promising DNA-binding ability and apoptosis caused G0/G1 phase arrest at sub-micromolar concentrations. To ascertain the binding mode and understand the structural requirement of DNA binding interaction, molecular docking studies using GOLD program and more rigorous 2 ns molecular dynamic simulations using Molecular Mechanics-Poisson-Boltzman Surface Area (MM-PBSA) approach including the explicit solvent were carried out. Further, the compound 17d was evaluated for in vivo efficacy studies in human colon cancer HT29 xenograft mice.

Design, synthesis and biological evaluation of imidazopyridine/pyrimidine-chalcone derivatives as potential anticancer agents

A new series of imidazo[2,1-b]pyridine/pyrimidine chalcone derivatives were synthesized and evaluated for their anticancer activity. These chalcone derivatives showed promising activity with GI50 values ranging from 0.28 to 30.0 μM. The detailed biological aspects of one of the promising compound 3f on the MCF-7 cell line were studied. Interestingly, compound 3f induced G1 cell cycle arrest, down regulation of G1 phase cell cycle regulatory proteins such as cyclin D1, E1, and CDK2. Moreover, compound 3f showed the characteristic features of apoptosis such as enhancement in the levels of p27 and TNFR1 proteins with concomitant down regulation of procaspase-9. One of the representative compound of this series 3f could be considered as the potential lead for its development as a new anticancer agent.

Quinazolinone linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates: Design, synthesis and biological evaluation as potential anticancer agents

A series of novel quinazolinone linked pyrrolobenzodiazepine (PBD) conjugates were synthesized. These compounds 4a-f and 5a-f were prepared in good yields by linking C-8 of DC-81 with quinazolinone moiety through different alkane spacers. These conjugates were tested for anticancer activity against 11 human cancer cell lines and found to be very potent anticancer agents with GI(50) values in the range of <0.1-26.2microM. Among all the PBD conjugates, one of the conjugate 5c was tested against a panel of 60 human cancer cells. This compound showed activity for individual cancer cell lines with GI(50) values of <0.1microM. The thermal denaturation studies exhibited effective DNA binding ability compared to DC-81 and these results are further supported by molecular modeling studies. The detailed biological aspects of these conjugates on A375 cell line were studied. It was observed that compounds 4b and 5c induced the release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent cell death. Further, these compounds when treated with A375 cells showed the characteristic features of apoptosis like enhancement in the levels of p53, p21 and p27 inhibition of cyclin dependent kinase-2 (CDK2) and suppression of NF-kappaB. Moreover, these two compounds 4b and 5c control the cell proliferation by regulating anti-apoptotic genes like (B-cell lymphoma 2) Bcl-2. Therefore, the data generated suggests that these PBD conjugates activate p53 and inhibit NF-kappaB and thereby these compounds could be promising anticancer agents with better therapeutic potential for the suppression of tumours.

Synthesis and biological evaluation of novel Mannich bases of 2-arylimidazo(2,1-b)benzothiazoles as potential anti-cancer agents

A new series of Mannich bases of 2-arylimidazo[2,1-b]benzothiazoles were synthesized and evaluated for their anti-cancer activity. These compounds showed better cytotoxicity activity with IC(50) values ranging from 2.8 to 8.0 μM in HepG2, MCF-7 and HeLa cell lines. Further mechanism aspects responsible for the anti-cancer activity of two promising compounds 3c and 3f in HepG2 cell line were studied. Interestingly, 3c, 3f induced G2/M cell cycle arrest with down regulation of cyclin B and up regulation of Chk2 protein. Moreover, compounds 3c, 3f also showed the characteristic features of apoptosis such as enhancement in the levels of caspase-3. Treatments with compounds led to a decrease in levels of vital cell proliferation proteins such as Jun (C-Jun, JunB), p38 MAPK, p-JNK and PKCα. The compound 3f of the series could be considered as the potential lead for its development as a novel anti-cancer agent.

Synthesis and biological evaluation of novel triazoles and isoxazoles linked 2-phenyl benzothiazole as potential anticancer agents

A new series of isoxazoles and triazoles linked 2-phenyl benzothiazole were synthesized and evaluated for their anticancer activity. These compounds have been tested for their cytotoxicity three cancer cell lines. Among the compounds tested, compound 5d showed good cytotoxicity against Colo-205 and A549 cells in comparison to standard control PMX 610(1). Further compound 5d has been tested for its apoptotic activity and its inhibitory activity against caspase and PARP proteins. Hence this compound has the potential that it can be selected for further biological studies.

Design, synthesis and biological evaluation of 3,5-diaryl-isoxazoline/isoxazole-pyrrolobenzodiazepine conjugates as potential anticancer agents

A series of 3,5-diaryl-isoxazoline/isoxazole linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared. These conjugates showed potent anticancer activity with GI(50) values in the range of <0.1-3.6 microM. Some of these PBD conjugates (6a-c) with promising anticancer activity were further investigated on the cell cycle distribution. Moreover, these PBD conjugates exhibited G0/G1 arrest, enhancement in the levels of p53 protein as well as mitochondrial-mediated intrinsic pathway, leading to release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent apoptotic cell death. Hence these PBD conjugates with 6a being the most potent one could be be taken up for preclinical studies either alone or in combination with existing therapies.

Synthesis and apoptosis inducing ability of new anilino substituted pyrimidine sulfonamides as potential anticancer agents

A series of anilino substituted pyrimidine sulfonamides were prepared and evaluated for their anticancer activity. These sulfonamides showed promising activity with IC(50) values ranging from 5.6 to 12.3 μM. The detailed biological aspects of some of the promising compounds (3d, 3e and 3g) on the K562 cell line were studied. Interestingly, compounds induced G1 cell cycle arrest and down regulation of G1 phase cell cycle regulatory proteins such as cyclin D1, CDK4. These compounds also exhibited inhibition of NF-κB as well as its downstream target gene Akt1 and the phosphorylated form of AKt ser 474 proteins. One of the representative compound 3e could be considered as the potential lead for its development as a new anticancer agent.

Synthesis of Imidazothiazole–Chalcone Derivatives as Anticancer and Apoptosis Inducing Agents

A new class of imidazo[2,1‐b]thiazole chalcone derivatives were synthesized and evaluated for their anticancer activity. These chalcone derivatives show promising activity, with log GI50 values ranging from −7.51 to −4.00. The detailed biological aspects of these derivatives toward the MCF‐7 cell line were studied. Interestingly, these chalcone derivatives induced G0/G1‐phase cell‐cycle arrest, down‐regulation of G1‐phase cell‐cycle regulatory proteins such as cyclin D1 and cyclin E1, and up‐regulation of CDK4. Moreover, these compounds elicit the characteristic features of apoptosis such as enhancement in the levels of p53, p21, and p27, suppression of NF‐κB, and up‐regulation of caspase‐9. One of these chalcone derivatives, 3 d, is potentially well suited for detailed biological studies, either alone or in combination with existing therapies.