Microtubule associated proteins as targets for anticancer drug development.

The dynamic equilibrium of tubulin-microtubule is an essential aspect of cell survivality. Modulation of this dynamics has become an important target for the cancer drug development. Tubulin exists in the alpha-beta dimer form which polymerizes to form microtubule and further depolymerizes back to tubulin dimer. The microtubule plays an essential role in mitosis and cell multiplication. Antitubulin drugs disturb the microtubule dynamics which is essentially required for DNA segregation and cell division during mitosis so killing the cancerous cells. Microtubule Associated Proteins (MAPs) interact with cellular cytoskeletal microtubules. MAPs bind to the either polymerized or depolymerized tubulin dimers within the cell and mostly causing stabilization of microtubules. Some of the tubulin binding drugs are in clinical use and others in clinical trial. MAPs inhibitors are also in clinical trial. Post-translational modification of lysine-40 either in histone or in alpha tubulin has an important role in gene expression and is balanced between histone deacetylases (HDACs) and histone acetyltransferases (HATs). HDAC inhibitors have the anticancer properties to form a drug for the treatment of cancer. They act by inducing cell cycle arrest and cell death. Some of the HDAC inhibitors are approved to be used as anticancer drug while others are under different phases of clinical trial. The present review updates on various MAPs, their role in cancer progression, MAPs inhibitors and their future prospects.

An improved synthesis of indanocine and antiproliferative activity of 2-benzylindanocine via microtubule destabilization.

Indanocine, a potent anticancer investigational drug of National Cancer Institute-USA, has been much discussed in recent years. Present communication aimed at total synthesis of indanocine and its close analogues. Total synthesis was improved by double yields than previously reported yields. Some of the benzylidene and 2-benzyl derivatives with free rotation at C2 position exhibited potential cytotoxicities against various human cancer cell lines. Five such analogues exhibited potential antiproliferative effect against HCT-116 and MIA PACA-2 cell lines. Benzylindanocine 12i induced microtubule destabilization by occupying colchicine binding pocket of ß-tubulin. It also exhibited anti-inflammatory activity by down-regulating IL-6 and TNF-α. In Ehrlich ascites carcinoma model, 12i reduced 78.4% of EAC tumour in Swiss albino mice at 90 mg/kg (i.p.) dose. Further, in in vivo safety studies, 12i was found to be safe to rodents up to 1,000 mg/kg dose. Concomitant anticancer and anti-inflammatory activity of benzylindanocine is distinctive, which suggests its further optimization for better efficacy and druggability.

Design, synthesis and drug resistance reversal potential of novel curcumin mimics Van D: Synergy potential of curcumin mimics.

Being crucial part of plant-based novel discovery of drug from natural resources, a study was done to explore the antibacterial potential of curcumin mimics in combination with antibiotics against multidrug resistant isolates of Pseudomonas aeruginosa. The best candidate Van D, a curcumin mimics reduced the MIC of tetracycline (TET) up to 16 folds against multidrug resistant clinical isolates. VanD further inhibited the efflux pumps as evident by ethidium bromide efflux and by in-silico docking studies. In another experiment, it was also found that Van D inhibits biofilm synthesis. This derivative kills the KG-P2, an isolate of P. aeruginosa in a time dependent manner, the post-antibiotic effect (PAE) of tetracycline was extended as well as mutant prevention concentration (MPC) of TET was also decreased. In Swiss albino mice, Van D reduced the proinflammatory cytokines concentration. In acute oral toxicity study, this derivative was well tolerated and found to be safe up to 1000 mg/kg dose. To the best of our knowledge, this is the first report on curcumin mimics as synergistic agent via inhibition of efflux pump.

A novel synthesis of 2-arylbenzimidazoles in molecular sieves-MeOH system and their antitubercular activity.

Arylbenzimidazoles have been synthesized as antimycobacterial agents. An efficient synthesis has been developed for 2-arylbenzimidazoles from o-phenylenediamines and aromatic aldehydes in molecular sieves-methanol system. The methodology is straightforward to get 2-arylbenzimidazoles (3a-3z) in excellent yields with high chemoselectivity over 2-aryl-1-benzylbenzimidazoles (4a-4z). All these benzimidazole analogues were evaluated against M. tuberculosis in BACTEC radiometric assay. The compounds 4y and 4z exhibited potential antitubercular activity against M. tuberculosis H37RV, MIC at 16 µM and 24 µM respectively. The best compound of the series i.e. compound 4y was well tolerated by Swiss-albino mice in acute oral toxicity. Compound 4y possessing a diarylbenzimidazole core, can further be optimized for better activity.

Antiproliferative efficacy of curcumin mimics through microtubule destabilization.

Curcumin possesses an attractive chemical structure with highly conjugated diferuloylmethane core. Curcumin mimics have been designed and prepared with an additional bridged phenyl ring in conjugation. Fourteen diverse analogues were evaluated against a panel of human cancer cell lines. The best analogue of the series i.e. compound 6a exhibited potent cytotoxicity against A431, epidermoid carcinoma cell line (IC50 = 1.5 µM) and DLD1, colorectal adenocarcinoma cell line (IC50 = 6.9 µM). In tubulin kinetics experiment, compound 6a destabilized polymerisation process (IC50 = 4.68 µM). In cell cycle analysis, compound 6a exerted G2/M phase arrest in A431 cells and induced apoptosis. In Ehrlich Ascites Carcinoma in Swiss-albino mice, compound 6a showed 78.6% tumour reduction at 80 mg/kg dose and 57% solid tumour reduction at 150 mg/kg dose. Further, in acute-oral toxicity experiment in rodent model, compound 6a was given in three different oral doses to Swiss albino mice. There were non-significant changes in various biochemical parameters and major body organs studied, including their absolute and relative weights. It was tolerable up to 300 mg/kg dose in Swiss-albino mice. The present study shows that the novel curcumin mimic 6a is a safe and efficacious anticancer compound. However, it needs to be optimized for better efficacy.

Anticancer activity of gallic acid template-based benzylidene indanone derivative as microtubule destabilizer.

Benzylidene indanones have been designed and synthesized from gallic acid, a plant phenolic acid as possible anticancer agent. The best analogue of the series, that is, 3-(3',4',5'-trimethoxyphenyl)-4,5,6-trimethoxy-2-(4˝-nitrobenzylidene)-indan-1-one (8) exhibited potent cytotoxicity (IC50 =3-10 µm) against several human cancer cell lines through microtubule destabilization (IC50 =1.54 µm) after occupying colchicine-binding site of ß-tubulin. In cell cycle analysis, compound 8 exerted G2/M phase arrest in both MCF-7 and MDA-MB-231 cells and induced apoptosis. It reduced 34.8% solid tumor in in vivo Ehrlich ascite carcinoma in Swiss albino mice at 30 mg/kg dose. In acute oral toxicity experiment, it was tolerable up to 300 mg/kg doses in Swiss albino mice. The lead compound 8 needs to be optimized for better activity.

Effect of ethanolic extract of Cyperus rotundus L. against isoprenaline induced cardiotoxicity.

Interruption of blood supply to the heart results in acute myocardial infarction (AMI), and further damages the heart muscles. Available drugs for the treatment MI have one or other side effects, and there is a need for development of better alternative drugs from herbal sources. Here, we evaluated cardioprotective effect of Cyperus rotundus on isoprenaline- induced myocardial infarction. Thirty five Wistar rats, aged 60-100 days with body wt. 150-200 g, pretreated with ethanolic extract of Cyperus rotundus L. (@ 250 and 500 mg/kg body wt.) orally before induction of myocardial necrosis by administrating isoprenaline (85 mg/kg, s.c.) on 19th and 20th day of the pretreatment period. The treated rats were examined for gross functioning of heart, heart weight/body wt. Ratio, and also observed histopathologically. Further, activities of various cardiac enzymes such as aspartate transaminase, alanine transaminase, creatinine kinase-myoglobulin, lactate dehydrogenase, and the gold marker troponin-I were also determined. The levels altered by isoproterenol were found to be restored significantly by the test extracts especially at higher dose. Biochemical observations viz., serum ALT (P <0.0001), AST (P <0.0001), creatine kinase-myoglobulin (CK-MB) (P <0.0001), LDH (P <0.0001) demonstrated significant cardioprotective activity of the ethanolic extract of C. rotundus (500 mg/kg body wt.), against isoprenaline induced myocardial infarction. These results were also substantiated by physical parameters and histopathological observations. All these results were comparable with that of two standard drugs metoprolol (10 mg/kg/day), ramipril (3 mg/kg/day) as well as polyherbal formulation Abana (50 mg/kg/day).