Utpal Nandi

Development and validation of a highly sensitive LC-ESI-MS/MS method for estimation of IIIM-MCD-211, a novel nitrofuranyl methyl piperazine derivative with potential activity against tuberculosis: Application to drug development

In the present study, a simple, sensitive, specific and rapid liquid chromatography (LC) tandem mass spectrometry (MS/MS) method was developed and validated according to the Food and Drug Administration (FDA) guidelines for estimation of IIIM-MCD-211 (a potent oral candidate with promising action against tuberculosis) in mice plasma using carbamazepine as internal standard (IS). Bioanalytical method consisted of one step protein precipitation for sample preparation followed by quantitation in LC-MS/MS using positive electrospray ionization technique (ESI) operating in multiple reaction monitoring (MRM) mode. Elution was achieved in gradient mode on High Resolution Chromolith RP-18e column with mobile phase comprised of acetonitrile and 0.1% (v/v) formic acid in water at the flow rate of 0.4mL/min. Precursor to product ion transitions (m/z 344.5/218.4 and m/z 237.3/194.2) were used to measure analyte and IS, respectively. All validation parameters were well within the limit of acceptance criteria. The method was successfully applied to assess the pharmacokinetics of the candidate in mice following oral (10mg/kg) and intravenous (IV; 2.5mg/kg) administration. It was also effectively used to quantitate metabolic stability of the compound in mouse liver microsomes (MLM) and human liver microsomes (HLM) followed by its in-vitro-in-vivo extrapolation.

Detailed account on activation mechanisms of ruthenium coordination complexes and their role as antineoplastic agents

Ruthenium (Ru) complexes are known for their promising anticancer activity presumably due to octahedral coordination geometry, slow ligand exchange rate, the range of different oxidation states and target specificity. This review article summarizes the physicochemical processes which are responsible for the selectivity of Ru complexes toward cancer cells over the normal cells. Emphasis has been given on the activation mechanism of Ru(III) complex administered as a prodrug and then the release of active species in an acidic environment of cancer cell through normal or photo induced hydrolysis or ligand oxidation. This article also elaborates how active Ru complex can be designed by their rate of hydrolysis, kinetics of ligand exchange, pKa of the aquated species. The article further articulates how Ru complexes inhibit tumor growth via multiple events such as transferrin/albumin binding, ROS generation, inhibition of glutathione-S-transferases and kinases and DNA intercalation. Based on the above understanding, examples of various Ru complexes with their in-vitro cell based cytotoxicity and mechanism of action have been described to make this review comprehensive for future Ru based anticancer drug development. In the end, comments have been made on some emerging concepts regarding lack of innertness of Ru(III) complexes vis-à-vis Ru(II) species.

Pharmacokinetics, pharmacodynamics and safety profiling of IS01957, a preclinical candidate possessing dual activity against inflammation and nociception

ABSTRACT In spite of unprecedented advances in modern systems of medicine, there is necessity for exploration of traditional plant based secondary metabolites or their semisynthetic derivatives which may results in better therapeutic activity, low toxicity and favourable pharmacokinetics. In this context, computational model based predictions aid medicinal chemists in rational development of new chemical entity having unfavourable pharmacokinetic properties which is a major hurdle for its further development as a drug molecule. Para‐coumaric acid (p‐CA) and its derivatives found to be have promising antiinflammatory and analgesic activity. IS01957, a p‐CA derivative has been identified as dual acting molecule against inflammation and nociception. Therefore, objective of the present study was to investigate pharmacokinetics, efficacy and safety profile based on in‐silico, in‐vitro and in‐vivo model to assess drug likeliness. In the present study, it has excellent pharmacological action in different animal models for inflammation and nociception. Virtual pharmacokinetics related properties of IS01957 have resemblance between envision and experimentation with a few deviations. It has also acceptable safety pharmacological profile in various animal models for central nervous system (CNS), gastro intestinal tract (GIT)/digestive system and cardiovascular system (CVS). Finally, further development of IS01957 is required based on its attractive preclinical profiles. HighlightsIS01957 have excellent drug likeliness as a preclinical candidate.It has dual activity against inflammation and nociception.It has resemblance in pharmacokinetics between envision and experimental outcomes.It has acceptable safety profile for CNS, CVS and GIT under experimental conditions.

Determination of ZSTK474, a novel Pan PI3K inhibitor in mouse plasma by LC–MS/MS and its application to Pharmacokinetics.

Graphical abstract Figure. No caption available. HighlightsSimple, robust, rapid, reproducible method development of ZSTK474 for routine analysis.Full validated LCMS/MS Method.Successfully applied to pharmacokinetics study.Mice pharmacokinetics is first time reported. ABSTRACT ZSTK474, a promising novel anticancer molecule derived from s‐triazine, found to have antitumor activities against different cancer cell lines. However, neither LCMS method nor pharmacokinetics of ZSTK474 has been reported till now. A sensitive, simple, short and specific liquid chromatography tandem mass spectrometry (LCMS/MS) method was developed for the quantification of ZSTK474 in mouse plasma accordance with the US Food and Drug Administration guidelines. Extraction of drug molecule was carried out using protein precipitation. Chromatographic analyte separation was achieved on Atlantis dC18 (4.6 × 50 mm, 3 &mgr;m). Composition of isocratic mobile phase consists of 90% acetonitrile and 0.2% formic acid, at 0.7 mL/min flow rate, having short 2.5 min run time. Method development was validated and found to be linear over a dynamic range between 1.9–1000 ng/mL; having a correlation coefficient (r 2) ≥ 0.9978. The analyte was found to be stable under short and long term storage conditions. LCMS/MS method developed was validated and found to be selective, reproducible, precise and accurate to quantify ZSTK474 in plasma samples, and first time successfully applied to pharmacokinetic studies. Pharmacokinetic data showed fast absorption attaining Cmax at 0.25 h and half life (t1/2) 5.18 h after oral administration of ZSTK474 at 20 mg/kg in mouse.

Re-Validation of New Develop Highly Sensitive, Simple LCMS/MS Method for the Estimation of Rohitukine and its Application in ADME/Pre-Clinical Pharmacokinetics

The purpose of the research was to develop a simple, rapid, accurate, reproducible and sensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for determination of Rohitukine, a chromone alkaloid in plasma. The chromatographic separation was achieved with high resolution RP18e Chromolith column (100 × 4.6 mm, 2 μm) employing a isocratic composition of organic solvent acetonitrile with 0.1% (v/v) formic acid (80:20, %v/v) at a flow rate of 0.5 mL/min. Triple quadrupole mass spectrometry with positive electrospray ionization (ESI) technique operating in multiple reaction monitoring used to estimate MS/MS ion transitions like 306.05>245.10 and 306.05>231.05 for Rohitukine and 330.30>97.0 for IS. Simple single step protein precipitate method was used for sample preparation. The method was validated for specificity, linearity, accuracy, precision, recovery, matrix effect and stability as per FDA guidelines. Linearity of the analyte was acquired throughout the concentration range from 0.1 ng/mL to 1000 ng/mL in mice plasma. Pharmacokinetic study was performed on female BALB/c mice through oral (20 mg/kg) and intravenous (2 mg/kg) route where the oral bioavailability of Rohitukine obtained was 84%. The bioanalytical method was successfully used for determination of plasma protein binding study, permeability and microsomal stability in mouse, rat and human liver microsomes.

Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model

In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.