Vijay K. Patel

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.

Pharmacophore Based 3D-QSAR, Virtual Screening and Docking Studies on Novel Series of HDAC Inhibitors with Thiophen Linker as Anticancer Agents

BACKGROUND Histone deacetylase (HDAC) inhibitors can reactivate gene expression and inhibit the growth and survival of cancer cells. OBJECTIVE To identify the important pharmacophoric features and correlate 3Dchemical structure with biological activity using 3D-QSAR and Pharmacophore modeling studies. METHOD The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. Pharmacophore hypothesis represents the 3D arrangement of molecular features necessary for activity. A series of 55 compounds with wellassigned HDAC inhibitory activity were used for 3D-QSAR model development. RESULTS Best 3D-QSAR model, which is a five partial least square (PLS) factor model with good statistics and predictive ability, acquired Q2 (0.7293), R2 (0.9811), cross-validated coefficient rcv 2=0.9807 and R2 pred=0.7147 with low standard deviation (0.0952). Additionally, the selected pharmacophore model DDRRR.419 was used as a 3D query for virtual screening against the ZINC database. In the virtual screening workflow, docking studies (HTVS, SP and XP) were carried out by selecting multiple receptors (PDB ID: 1T69, 1T64, 4LXZ, 4LY1, 3MAX, 2VQQ, 3C10, 1W22). Finally, six compounds were obtained based on high scoring function (dock score -11.2278-10.2222 kcal/mol) and diverse structures. CONCLUSION The structure activity correlation was established using virtual screening, docking, energetic based pharmacophore modelling, pharmacophore, atom based 3D QSAR models and their validation. The outcomes of these studies could be further employed for the design of novel HDAC inhibitors for anticancer activity.

Drug Design Strategies for the Discovery of Novel Anticonvulsants Concerned with Four Site Binding Pharmacophoric Model Studies.

Anticonvulsant refers to a group of pharmaceuticals used in the treatment of epileptic seizures. The use of current antiepileptic drugs has been questioned due to the non-selectivity of the drugs and the undesirable side effects produced by them. This led to the search for antiepileptic compounds with more selectivity and lower toxicity. Semicarbazones have been developed as versatile anticonvulsant pharmacophore. It has displayed potent anticonvulsant effect in a wide variety of preclinical anticonvulsant models. Till date various semicarbazone derivatives containing 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyrimidine, benzothiazole and substituted phenyl/aryl ring have been synthesized and evaluated for anticonvulsant activity. The semicarbazone based pharmacophore model with four binding sites is essential for anticonvulsant activity. This model comprises of an aryl hydrophobic binding site, hydrogen bonding domain, an electron donor group and another hydrophobic-hydrophilic site regulating the pharmacokinetic properties of the anticonvulsant. Extensive structure-activity relationship has demonstrated that compound with OH, CH3O, NO2, Cl, F, Br substituents in the arylhydrophobic pocket, nitro, hydroxy group on distant phenyl ring and a hydrogen bonding domain possess anticonvulsant activity. In this review, advances made in the application of semicarbazones as a versatile pharmacophore model for the design of new anticonvulsant drugs are being updated and suggested for future drug design and development of novel anticonvulsants.

Synthesis, biological evaluation and molecular docking studies of 2-amino-3,4,5-trimethoxyaroylindole derivatives as novel anticancer agents

A series of novel 2-amino-3,4,5 trimethoxyaroylindole derivatives was synthesized and evaluated against selected human cancer cell lines of breast (MCF-7) and colon (HT-29). Introduction of an amino group at the C-2 position on ring A of 3,4,5-trimethoxyaroylindole derivatives resulted in novel compounds, i.e., 2-amino-3,4,5-trimethoxyaroylindole derivatives exhibiting excellent cytotoxic activity against human cancer cell lines. Substitution with methoxy group at R(6) in 2-amino-3,4,5-trimethoxyaroylindole 5d exhibited excellent cytotoxic activity against MCF-7 (0.013 μM) and colon HT-29 (0.143 μM) indicating slightly higher potency than Combretastatin A-4. Molecular modeling studies of 2-amino-3,4,5-trimethoxyaroylindole derivatives have similar structural alignment as colchicine in protein (PDB code: 1SA0) and exhibited hydrogen bond interaction between para position of 3,4,5-trimethoxyphenyl ring with CYS 241 and N-H molecule of indole ring with Val 315 of receptor molecule.

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.

Histone Deacetylase Inhibitors for the Treatment of Colorectal Cancer: Recent Progress and Future Prospects

BACKGROUND Colorectal cancer is a devastating disease with a dismal prognosis which is heavily hampered by delayed diagnosis. Surgical resection, radiation therapy and chemotherapy are the curative options. Due to few therapeutic treatments available i.e., mono and combination therapy and development of resistance towards drug response, novel and efficacious therapy are urgently needed. OBJECTIVE In this study, we have studied the potential of histone deacetylase inhibitors in colorectal cancer. RESULTS Histone deacetylase inhibitors (HDACIs) are an emerging class of therapeutic agents having potential anticancer activity with minimal toxicity for different types of malignancies in preclinical studies. HDACIs have proven less effective in monotherapy thus the combination of HDACIs with other anticancer agents are being assessed for the treatment of colorectal cancer. CONCLUSION The molecular mechanism emphasizing the anticancer effect of HDACIs in colorectal cancer was illustrated and a recapitulation was carried out on the recent advances in the rationale behind combination therapies currently underway in clinical evaluations.

Novel Pyrimidine based Semicarbazones: Confirmation of Four Binding Site Pharmacophoric Model Hypothesis for Antiepileptic Activity

BACKGROUND Epilepsy is a neurological disorder, characterized by seizures accompanied by loss or disturbance of consciousness affecting various physical and mental functions. Current anticonvulsant drugs are effective in controlling seizures in about 70% of cases, but their use is often limited by side effects like ataxia, megaloblastic anemia, hepatic failure. In search for a novel anticovulsant drug with better efficacy and lower toxicity, a series of novel pyrimidine based semicarbazone were designed and evaluated for antiepileptic activity. METHODS The test compounds were designed on the basis of four site binding hypothesis proposed for anticonvulsant activity. The chemical structures of the test compounds were elucidated using spectral (IR, 1H NMR, 13C NMR and MS) and elemental analysis. The minimal motor impairment activity was determined in mice using rotorod test. The maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models were employed for anticonvulsant evaluation. RESULTS The results reveal that 76% of the compounds were active in the MES screening as compared to 53% of the compounds in the scPTZ test. Test compounds showed some MES selectivity displaying their effectiveness in generalized seizures of the tonic-clonic type. The molecular docking analysis of semicarbazone derivatives showed good ligand-receptor interactions with specially hydrogen bond interactions with ARG192, GLU270 and THR353 amino acid of receptor. CONCLUSION The present report confirms that pharmacophore model with four binding sites is crucial for anticonvulsant activity in the semicarbazones.

Bioanalytical Method Development and Validation for the Determination of Levocetirizine in Pharmaceutical Dosage Form and Human Plasma by RP-HPLC -

This study describes the development of a rapid, selective, precise and sensitive reverse phase high-performance liquid chromatography method for the quantitative determination of Levocetirizine Dihydrochloride (LCD) in human plasma and pharmaceutical dosage form. Extraction of drug from plasma was done by employing optimized liquid-liquid extraction procedure. The sample was analyzed using Acetonitrile: Methanol: 20mM Ammonium Acetate Buffer pH-5 (25:55:20 % v/v/v) as mobile phase. Chromatographic separation was achieved on Prontosil C-18 column (4.6 x 250mm, 5μ particle size) as stationary phase using isocratic elution (at a flow rate of 1 mL/min). The peak was detected using UV-PDA detector set at 232 nm and the total time for a chromatographic separation was 8 min. The calibration curve obtained was linear (r2= 0.9998) over the concentration range of 2-10 μg/mL. Method was validated for precision, robustness and recovery. The limit of detection (LOD) and limit of quantitation (LOQ) was 0.0057 and 0.174 µg/mL respectively. There was no significant difference between the amount of drug spiked in plasma and the amount recovered and plasma did not interfere in estimation. Thus, the proposed method is suitable for the analysis of LCD in tablet dosage forms and human plasma.

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.