A Rationally Designed Bimetallic Platinum (II)-Ferrocene Antitumor Agent Induces Non-Apoptotic Cell Death and Exerts in Vivo Efficacy.

Despite phenomenal clinical success, the efficacy of platinum anticancer drugs is often compromised due to inherent and acquired drug resistant phenotypes in cancers. To circumvent this issue, we designed two heterobimetallic platinum (II)-ferrocene hybrids that display multi-pronged anticancer action. In cancer cells, our best compound, 2, platinates DNA, produces reactive oxygen species, and has nucleus, mitochondria, and endoplasmic reticulum as potential targets. The multi-modal mechanism of action of these hybrid agents lead to non-apoptotic cell death induction which enables circumventing apoptosis resistance and significant improvement in platinum cross resistance profile. Finally, in addition to describing detail mechanistic insights, we also assessed its stability in plasma and demonstrate anticancer efficacy in an in vivo A2780 xenograft model. Strikingly, compared to oxaliplatin, our compound displays better tolerability, safety profile and efficacy in vivo.

Synthesis, biological evaluation, and molecular docking analysis of phenstatin based indole linked chalcones as anticancer agents and tubulin polymerization inhibitors.

A library of new phenstatin based indole linked chalcone compounds (9a-z and 9aa-ad) were designed and synthesized. Of these, compound 9a with 1-methyl, 2- and 3-methoxy substituents in the aromatic ring was efficacious against the human oral cancer cell line SCC-29B, spheroids, and in a mouse xenograft model of oral cancer AW13516. Compound 9a exhibited anti-cancer activity through disrupting cellular integrity and affecting glucose metabolism-which is a hallmark of cancer. The cellular architecture was affected by inhibition of tubulin polymerization as observed by an immunofluorescence assay on 9a-treated SCC-29B cells. An in vitro tubulin polymerization kinetics assay provided evidence of direct interaction of 9a with tubulin. This physical interaction between tubulin and compound 9a was further confirmed by Surface Plasmon Resonance (SPR) analysis. Molecular docking experiments and validations revealed that compound 9a interacts and binds at the colchicine binding site of tubulin and at active sites of key enzymes in the glucose metabolism pathway. Based on in silico modeling, biophysical interactions, and pre-clinical observations, 9a consisting of phenstatin based indole-chalcone scaffolds, can be considered as an attractive tubulin polymerization inhibitor candidate for developing anti-cancer therapeutics.

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.

Seaweed polysaccharide derived bioaldehyde nanocomposite: Potential application in anticancer therapeutics.

In the present study, we have demonstrated synthesis of agar aldehyde (Aald) from seaweed polysaccharide and its further successful application for preparation of Aald mediated solid silver nanocomposite (Aald-AgNPs). Aald-AgNPs were characterized for biophysical properties by FTIR, XRD, SEM, TEM, XPS, and UV-vis spectroscopy. Aald-AgNPs were further tested in vitro and in vivo for anticancer activity. The results of the in vitro study revealed that Aald-AgNPs exhibited activity against 3 cancer cell lines. Aald-AgNPs were found to act through causing dose dependent increase in cell size, inducing anueploidy, mitochondrial disintegration and increasing septa formation in cell cytoplasm. Results of in vivo anticancer activity against ME-180, Colon-26, and HL-60 xenograft mice tumor models showed 64 %, 27.3 % and 51 % reduction in tumor volume, respectively with 83-100 % survival rate. Aald-AgNPs exhibited excellent antibacterial activity. It was interesting to note that Aald-AgNPs did not exhibit any significant detrimental effect on viability and metabolic activity of normal bone marrow derived mesenchymal stem cells. This study opens new areas of research for chemists and biologists to use seaweed-derived polymers to develop nanocomposites for cancer therapeutics.

Remarkable DNA binding affinity and potential anticancer activity of pyrrolo[2,1-c][1,4]benzodiazepine-naphthalimide conjugates linked through piperazine side-armed alkane spacers.

A series of pyrrolobenzodiazepine-naphthalimide conjugates tethered through a piperazine ring system have been designed, synthesized, and evaluated for their anticancer activity. These new conjugates exhibit very high DNA binding affinity and cytotoxic activity against a number of cell lines.

Design, synthesis and biological evaluation of novel pyrazolochalcones as potential modulators of PI3K/Akt/mTOR pathway and inducers of apoptosis in breast cancer cells.

Cancer has been established as the "Emperor of all maladies". In recent years, medicinal chemistry has focused on identifying novel anti-cancer compounds; though discovery of these compounds appears to be a herculean task. In present study, we synthesized forty pyrazolochalcone conjugates and explored their cytotoxic activity against a panel of sixty cancer cell lines. Fifteen conjugates of the series showed excellent growth inhibition (13b-e, 13h-j, 14c-d, 15 a, 15 c-d, 16b, 16d and 18f; GI50 for MCF-7: 0.4-20 µM). Conjugates 13b, 13c, 13d, 16b and 14d were also evaluated for their cytotoxic activity in human breast cancer cell line (MCF-7). The promising candidates induced cell cycle arrest, mitochondrial membrane depolarization and apoptosis in MCF-7 cells at a 2 µM concentration. Furthermore, inhibition of PI3K/Akt/mTOR pathway-regulators such as PI3K, p-PI3K, p-AKT, and mTOR were observed; as well as upregulation of p-GSK3ß and tumor-suppressor protein, PTEN. Our study indicates that pyrazolochalcone conjugates could serve as potential leads in the development of tailored cancer therapeutics.

Synthesis, DNA binding, and cytotoxicity studies of pyrrolo[2,1-c][1,4]benzodiazepine-anthraquinone conjugates.

A series of pyrrolo[2,1-c][1,4]benzodiazepine-anthraquinone conjugates have been prepared and evaluated for their DNA binding ability as well as anticancer activity. Some of these molecules have shown significant anticancer activity in a number of cancer cell lines.