Kokkonda Sreekanth

Synthesis of new benzimidazole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates with efficient DNA-binding affinity and potent cytotoxicity

The synthesis of new benzimidazole linked pyrrolobenzodiazepine conjugates is described. Some of these conjugates show significant DNA-binding affinity and, a representative compound 4c shows promising in vitro cytotoxicity against a number of human cancer cell lines.

Synthesis and biological evaluation of cinnamido linked pyrrolo[2,1-c][1,4]benzodiazepines as antimitotic agents

A series of new cinnamido-pyrrolo[2,1-c][1,4]benzodiazepine conjugates (4a-d and 5a-d) and their dimers (6a-d) have been designed, synthesized and evaluated for their biological activity. The anticancer screening of compound 4a by the NCI exhibited significant GI50 values ranging from 68 to 732 nM against 53 of 59 human cancer cell lines tested. Compounds 5a-d and 6a-d have also shown remarkable cytotoxic activity with GI50 values <0.1 microM concentrations in a large number of cell lines. Interestingly, compounds 5b and 6b have been identified as a new class of inhibitors of tubulin polymerization and their action has been rationalized by the cell cycle arrest in G0 and G2/M phase.

Synthesis and potential cytotoxic activity of new phenanthrylphenol-pyrrolobenzodiazepines

New phenanthrylphenol-pyrrolobenzodiazepine (PP-PBD) conjugates have been synthesized and evaluated for their biological activity. One of the compounds 4a has been evaluated for its antiproliferative activity on 57 human tumour cell lines. The growth inhibition of 4a-c has been determined by MTT viability assay on MCF-7 cell line. Among them, 4c showed most potent growth inhibition. Based on this, an attempt was made to rationalize their mechanism of action through cell cycle analysis and DNA interaction studies. The effect of the lead compound 4c on MCF-7 cell growth associated with cell cycle arrest in G1 phase, followed by apoptosis. Our findings suggested the phenanthrylphenol-PBD conjugate 4c, which is a cyclin D1 inhibitor could be considered as a promising lead compound against breast cancer for further investigation.

A one-pot azido reductive tandem mono-N-alkylation employing dialkylboron triflates: online ESI-MS mechanistic investigation.

An efficient one-pot reductive tandem mono-N-alkylation of both aromatic and aliphatic azides using dialkylboron triflates as alkylating agents has been examined under standardized reaction conditions. This methodology after optimization has been employed toward the syntheses of various secondary alkyl as well as aryl amines, including the synthesis of N10-butylated pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones via in situ azido reductive-cyclization process. This protocol is particularly attractive to provide an environmentally benign and practical method for mono-N-alkylation from organic azides without the use of toxic catalysts or corrosive alkylating agents. In addition, the mechanistic aspects have been investigated and the intermediates associated with this selective transformation have been intercepted and characterized by online monitoring of the reaction by ESI-MS/MS.

Dithiocarbamate/piperazine bridged pyrrolobenzodiazepines as DNA-minor groove binders: Synthesis, DNA-binding affinity and cytotoxic activity

A new series of C8-linked dithiocarbamate/piperazine bridged pyrrolo[2,1-c][1,4]benzodiazepine conjugates (5a-c, 6a,b) have been synthesized and evaluated for their cytotoxic potential and DNA-binding ability. The representative conjugates 5a and 5b have been screened for their cytotoxicity against a panel of 60 human cancer cell lines. Compound 5a has shown promising cytotoxic activity on selected cancer cell lines that display melanoma, leukemia, CNS, ovarian, breast and renal cancer phenotypes. The consequence of further replacement of the 3-cyano-3,3-diphenylpropyl 1-piperazinecarbodithioate in 5b and 5c with 4-methylpiperazine-1-carbodithioate yielded new conjugates 6a and 6b respectively. In addition, the compounds 5c and 6a,b have been evaluated for their in vitro cytotoxicity on some of the selected human cancer cell lines and these conjugates have exhibited significant cytotoxic activity. Further, the DNA-binding ability of these new conjugates has been evaluated by using thermal denaturation (ΔTm) studies. The correlation between structure and DNA-binding ability has been investigated by molecular modeling studies which predicted that 6b exhibits superior DNA-binding ability and these are in agreement with the experimental DNA-binding studies.

Synthesis, DNA Binding Ability and Anticancer Activity of 2-heteroaryl Substituted Benzimidazoles Linked Pyrrolo[2,1-c][1,4]benzodiazepine Conjugates

As a continuation of our efforts to develop the benzimidazole-PBD conjugates as potential anticancer agents, a series of heteroaryl substituted benzimidazole linked PBD conjugates has been synthesized and evaluated for their anticancer potential in 60 human cancer cell lines. Most of the compounds exhibited promising anticancer activity and interestingly, compounds 4c and 4d displayed significant activity in most of the cell lines tested. Whereas, compound 4e showed selectivity in renal cancer cells with GI50 values of <10 and 70 nM against RXF 393 and UO-31 cell lines, respectively. Further, these compounds also showed significant DNA-binding affinity by thermal denaturation study using duplex form of calf thymus (CT) DNA.