Deepak Kumar Jain

Design of Combretastatin A-4 Analogs as Tubulin Targeted Vascular Disrupting Agent with Special Emphasis on Their Cis-Restricted Isomers

Tubulin protein is a highly imperative and feasible goal for anticancer drug discovery. Hundreds of naturally occurring, semi synthetic and synthetic antitubulin agents have been reported till now. Among these, Combretastatin A - 4 (CA - 4) is effective antimitotic agent possessing potent cytotoxicity against a panel of cancer cells, including multi-drug resistant cancer cell lines. The inadequate water solubility and inactivation of these analogs during storage limit their use as clinical anticancer agents. To overcome these shortcomings, numerous water soluble amino analogs, amino acid derivative, phosphate prodrug (CA - 4P) and cis-locked CA - 4 have been developed with distinctive attributes of antitubulin and antivascular properties in a wide variety of preclinical tumor models. Subsequently, several heterocycle based cis restricted CA - 4 analogs are being reported for antitumor activity against collection of cancer cell lines. This review recapitulates the rational design, structure activity relationship, pharmacokinetic and pharmacodynamic profile of synthesized cis restricted CA - 4 analogs.

Ebola virus disease: past, present and future

Ebola virus disease is one of the most deadly ailments known to mankind due to its high mortality rate (up to 90%) accompanying with the disease. Ebola haemorrhagic fever (EHF) is an infectious disease of animal that can be transmitted to both human and non-human primates. The first epidemic of EHF occurred in 1976 in the Democratic Republic of the Congo. The incubation period of ebola is less than 21 days. Ebola virus infections are depicted by immune suppression and a systemic inflammatory response that leads to damage of the vascular, coagulation and immune systems, causing multi-organ failure and shock. Five genetically distinct members of the Filoviridae family responsible for EHF are as follows: Zaire ebolavirus, Sudan ebolavirus, Cote d’Ivoire ebolavirus, Bundibugyo ebolavirus and Reston ebolavirus. The ongoing 2014 West Africa ebola epidemic has been considered as the most serious panic in the medical field with respect to both the number of human cases and death toll. The natural host for ebola virus is unknown, thus it is not possible to carry out programs to regulate or abolish virus from transmission to people. The ebola virus infection provides little chance to develop acquired immunity causing rapid progression of the disease. It is pertinent to mention that at present, there is no antiviral therapy or vaccine that is helpful against ebola virus infection in humans. The impediment of EHF necessitates much better understanding of the epidemiology of the disease, particularly the role of wildlife, as well as bats, in the spread of ebola virus to humans.

Panobinostat as Pan-deacetylase Inhibitor for the Treatment of Pancreatic Cancer: Recent Progress and Future Prospects

The histone deacetylase (HDAC) inhibitors have been demonstrated as an emerging class of anticancer drugs. HDACs are involved in regulation of gene expression and in chromatin remodeling, thus indicating valid targets for different types of cancer therapeutics. The pan-deacetylase inhibitor panobinostat (Farydac®, LBH589) was developed by Novartis Pharmaceuticals and has been recently approved by the US Food and Drug Administraion (FDA) as a drug to treat multiple myeloma. It is under clinical investigation for a range of haematological and solid tumors worldwide in both oral and intravenous formulations. Panobinostat inhibits tumor cell growth by interacting with acetylation of histones and non-histone proteins as well as various apoptotic, autophagy-mediated targets and various tumorogenesis pathways involved in development of tumors. The optimal combination regimen for pancreatic cancer remains to be fully elucidated with various combination regimens, and should be investigated in clinical trials. This article summarizes the current preclinical and clinical status of panobinostat in pancreatic cancer. Preclinical data suggests that panobinostat has potential inhibitory activity in pancreatic cancer cells by targeting various pathways and factors involved in the development of cancer. Herein, we reviewed the status of mono and combination therapy and the rationale behind the combination therapy undergoing trials, as well as possible future prospective use in the treatment of pancreatic cancer.

The Safety, Efficacy and Therapeutic Potential of Histone Deacetylase Inhibitors with Special Reference to Panobinostat in Gastrointestinal Tumors: A Review of Preclinical and Clinical Studies.

Histone deacetylase inhibitors (HDACi) have been demonstrated as an emerging class of anticancer drugs involved in regulation of gene expression and chromatin remodeling thus indicating valid targets for different types of cancer therapeutics. The pan-deacetylase inhibitor panobinostat (Farydac®, LBH589) is developed by Novartis Pharmaceuticals and a newly US FDA approved drug for the multiple myeloma. It is under clinical investigation for a range of hematological and solid tumors worldwide in both oral and intravenous formulations. Panobinostat inhibits tumor cell growth by interacting with acetylation of histones and nonhistone proteins as well as various apoptotic, autophagy-mediated targets and various tumorigenesis pathways involved in the development of cancer. The current article summarizes the status of panobinostat in gastrointestinal cancers. Preclinical and clinical data suggest that panobinostat has potential inhibitory activity in hepatocellular, pancreatic, colorectal, gastric and gastrointestinal stromal tumors. Clinical evaluations of panobinostat are currently underway. Herein, we have also reviewed the rationale behind the combination therapy under the trials and possible future prospective for the treatment of GI tumors.

Assessment of 5-substituted Isatin as Surface Recognition Group: Design, Synthesis, and Antiproliferative Evaluation of Hydroxamates as Novel Histone Deacetylase Inhibitors

Histone deacetylase (HDAC) is a promising target for cancer treatment. HDAC inhibitors consist of three pharmacophoric features: an aromatic cap group, zinc binding group (ZBG), and a linker chain connecting cap group to ZBG. Herein, we report on (i) substituted isatin moiety as the cap group that recognizes the surface of active enzyme pocket and (ii) thiosemicarbazide moiety incorporated as linker group responsible for connecting the cap group to ZBG (hydroxamic acid). The synthesized compounds were evaluated for their antiproliferative activity and HDAC enzyme inhibition. The binding mode analysis of proposed compounds was evaluated by docking studies. Several analogs were found to inhibit HDAC and cellular proliferation of Hela cervical cancer cells, with GI50 values in the micromolar range. One compound (Vd) was found to have greater in vitro antiproliferative activity in comparison to other compounds.