Pharmaceutical Sciences and Natural Products - Research Publications
Permanent URI for this collectionhttps://kr.cup.edu.in/handle/32116/56
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Item Polycystic ovary syndrome: Current scenario and future insights(Elsevier Ltd, 2023-11-05T00:00:00) Kulkarni, Swanand; Gupta, Khushi; Ratre, Pooja; Mishra, Pradyumna Kumar; Singh, Yogesh; Biharee, Avadh; Thareja, SureshPolycystic ovary syndrome (PCOS) prevails in approximately 33% of females of reproductive age globally. Although the root cause of the disease is unknown, attempts are made to clinically manage the disturbed hormone levels and symptoms arising due to hyperandrogenism, a hallmark of PCOS. This review presents detailed insights on the etiology, risk factors, current treatment strategies, and challenges therein. Medicinal agents currently in clinical trials and those in the development pipeline are emphasized. The significance of the inclusion of herbal supplements in PCOS and the benefits of improved lifestyle are also explained. Last, emerging therapeutic targets for treating PCOS are elaborated. The present review will assist the research fraternity working in the concerned domain to access significant knowledge associated with PCOS. � 2023 Elsevier LtdItem Boron in cancer therapeutics: An overview(Elsevier Inc., 2023-10-17T00:00:00) Kulkarni, Swanand; Bhandary, Dyuti; Singh, Yogesh; Monga, Vikramdeep; Thareja, SureshBoron has become a crucial weapon in anticancer research due to its significant intervention in cell proliferation. Being an excellent bio-isosteric replacement of carbon, it has modulated the anticancer efficacy of various molecules in the development pipeline. It has elicited promising results through interactions with various therapeutic targets such as HIF-1?, steroid sulfatase, arginase, proteasome, etc. Since boron liberates alpha particles, it has a wide-scale application in Boron Neutron Capture therapy (BNCT), a radiotherapy that demonstrates selectivity towards cancer cells due to high boron uptake capacity. Significant advances in the medicinal chemistry of boronated compounds, such as boronated sugars, natural/unnatural amino acids, boronated DNA binders, etc., have been reported over the past few years as BNCT agents. In addition, boronated nanoparticles have assisted the field of bio-nano medicines by their usage in radiotherapy. This review exclusively focuses on the medicinal chemistry aspects, radiotherapeutic, and chemotherapeutic aspects of boron in cancer therapeutics. Emphasis is also given on the mechanism of action along with advantages over conventional therapies. � 2023 Elsevier Inc.Item Developing our knowledge of the quinolone scaffold and its value to anticancer drug design(Taylor and Francis Ltd., 2023-08-18T00:00:00) Singh, Yogesh; Bhatia, Neha; Biharee, Avadh; Kulkarni, Swanand; Thareja, Suresh; Monga, VikramdeepIntroduction: The quinolone scaffold is a bicyclic benzene-pyridinic ring scaffold with nitrogen at the first position and a carbonyl group at the second or fourth position. It is endowed with a diverse spectrum of pharmacological activities, including antitumor activity, and has progressed into various development phases of clinical trials for their target-specific anticancer activity. Areas covered: The present review covers both classes of quinolones, i.e. quinolin-2(H)-one and quinolin-4(H)-one as anticancer agents, along with their possible mode of binding. Furthermore, their structure-activity relationships, molecular mechanisms, and pharmacokinetic properties are also covered to provide insight into their structural requirements for their rational design as anticancer agents. Expert opinion: Synthetic feasibility and ease of derivatization at multiple positions, has allowed medicinal chemists to explore quinolones and their chemical diversity to discover newer anticancer agents. The presence of both hydrogen bond donor (?NH) and acceptor (-C=O) functionality in the basic scaffold at two different positions, has broadened the research scope. In particular, substitution at the -NH functionality of the quinolone motif has provided ample space for suitable functionalization and appropriate substitution at the quinolone�s third, sixth, and seventh carbons, resulting in selective anticancer agents binding specifically with various drug targets. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Thioether linkage chemistry: perspectives and prospects in therapeutic designing(Elsevier, 2023-07-07T00:00:00) Singh, Yogesh; Kulkarni, Swanand; Thareja, SureshPolymer�drug conjugates (PDCs) are an emerging approach for the development of targeted drug delivery systems for chemotherapeutic agents possessing poor pharmacokinetic properties. Development of PDCs offers an advantage of optimization to a certain extent to formulation as well as medicinal chemists via linking bioactive drug molecule to polymeric linker. Formulation of a drug in PDCs generally enhances the pharmacokinetic parameters of a drug by increasing its bioavailability. Also, controlled and target-specific drug release helps to reduce the adverse effects associated with off-target binding of the drugs. In this chapter, readers will be able to understand thoroughly the concept of PDCs, linkers used in the preparation of PDCs, their types, and various examples of PDCs that are reportedly found to be potent in the diseases they were intended to show activity. � 2023 Elsevier Inc. All rights reserved.Item Phosphate Prodrugs: An Approach to Improve the Bioavailability of Clinically Approved Drugs(Bentham Science Publishers, 2023-02-09T00:00:00) Tantra, Tanmoy; Singh, Yogesh; Patekar, Rohan; Kulkarni, Swanand; Kumar, Pradeep; Thareja, SureshThe phosphate prodrug approach has emerged as a viable option for increasing the bioavailability of a drug candidate with low hydrophilicity and poor cell membrane permeability. When a phosphoric acid moiety is attached to the parent drug, it results in a several-fold elevation in aqueous solubility which helps to achieve desired bioavailability of the pharmaceutically active parental molecule. The neutral phosphate prodrugs have rapid diffusion ability through the plasma membrane as compared to their charged counterpart. The presence of phosphate mono ester breaking alkaline phosphatase (ALP) enzyme throughout the whole human body, is the main consideration behind the development of phosphate prodrug strategy. The popularity of this phosphate prodrug strategy is increasing nowadays due to the fulfillment of different desired pharmacokinetic characteristics required to get pharmaceutical and therapeutic responses without showing any serious adverse drug reactions (ADR). This review article mainly focuses on various phosphate prodrugs synthesized within the last decade to get an improved pharmacological response of the parent moiety along with various preclinical and clinical challenges associated with this approach. Emphasis is also given to the chemical mechanism to release the parent moiety from the prodrug. � 2024 Bentham Science Publishers.Item Molecular docking, 3D-QSAR and simulation studies for identifying pharmacophoric features of indole derivatives as 17?-hydroxysteroid dehydrogenase type 5 (17?-HSD5) inhibitors(Taylor and Francis Ltd., 2023-02-06T00:00:00) Kulkarni, Swanand; Singh, Yogesh; Biharee, Avadh; Bhatia, Neha; Monga, Vikramdeep; Thareja, SureshExcess of androgens leads to various diseases such as Poly-Cystic Ovarian Syndrome, Prostate Cancer, Hirsutism, Obesity and Acne. 17?-Hydroxysteroid Dehydrogenase type 5 (17?-HSD5) converts androstenedione into testosterone peripherally, thereby significantly contributing to the development of these diseases. Indole-bearing scaffolds are reported as potential 17?-HSD5 inhibitors for the manifestation of diseases arising due to androgen excess. In the present work, we have extensively performed a combination of molecular docking, Gaussian field-based 3D-QSAR, Pharmacophore mapping and MD-simulation studies (100 ns) to identify the pharmacophoric features of indole-based compounds as potent 17?-HSD5 inhibitors. Molecular simulation studies of the most potent compound in the binding pocket of enzyme revealed that the compound 11 was stable in the binding pocket and showed good binding affinity through interactions with various residues of active site pocket. The Molecular mechanics Generalized Born surface area continuum solvation (MM/GBSA) and Molecular mechanics Poisson�Boltzmann surface area (MM/PBSA) calculations revealed that the compound 11 possessed a free binding energy of ?36.36 kcal/mol and ?7.00 kcal/mol, respectively, which was better as compared to reference compound Desmethyl indomethacin (DES). The developed pharmacophore will be helpful to design novel indole-based molecules as potent 17?-HSD5 inhibitors for the treatment of various androgenic disorders. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Medicinal chemistry aspects and synthetic strategies of coumarin as aromatase inhibitors: an overview(Springer, 2022-12-05T00:00:00) Ratre, Pooja; Kulkarni, Swanand; Das, Sweety; Liang, Chengyuan; Mishra, Pradyumna Kumar; Thareja, SureshCoumarin is a bicyclic oxygen bearing heterocyclic scaffold formed by fusion of benzene with the pyrone ring. Because of its unique physicochemical characteristics and the ease with which it may be transformed into a wide range of functionalized coumarins during�synthesis, coumarin provides a privileged scaffold for medicinal chemists. As a result, many coumarin derivatives have been developed, synthesized, and evaluated to target a variety of therapeutic domains, thereby making it an attractive template for designing novel anti-breast cancer compounds. The main culprit in estrogen overproduction in the estrogen-dependent breast cancer (EDBC), is the enzyme aromatase (AR), and it is thought to be a significant target for the effective treatment of EDBC. Considering coumarins versatility, this review presents a detailed overview of diverse study of aromatase as a target for coumarins. An overview of structure�activity relationship analysis of coumarin core is also included so as to summarize the desired pharmacophoric features essential for design and development of aromatase inhibitors (AIs) using coumarin core. Identification of key synthesis techniques that could aid researchers in designing and developing novel analogues with significant anti-breast cancer properties along with their mechanism of action have also been covered in the current review. Graphical Abstract: [Figure not available: see fulltext.] � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Recent Advancements in the Discovery of MDM2/MDM2-p53 Interaction Inhibitors for the Treatment of Cancer(Bentham Science Publishers, 2022-11-16T00:00:00) Bhatia, Neha; Khator, Rakesh; Kulkarni, Swanand; Singh, Yogesh; Kumar, Pradeep; Thareja, SureshDiscovery of MDM2 and MDM2-p53 interaction inhibitors changed the direction of anticancer research as it is involved in about 50% of cancer cases globally. Not on-ly the inhibition of MDM2 but also its interaction with p53 proved to be an effective strategy in anticancer drug design and development. Various molecules of natural as well as synthetic origin have been reported to possess excellent MDM2 inhibitory potential. The present review discusses the pathophysiology of the MDM2-p53 interaction loop and MDM2/MDM2-p53 interaction inhibitors from literature covering recent patents. Focus has also been put on characteristic features of the active site of the target and its desired interactions with the currently FDA-approved inhibitor. The designing approach of previ-ously reported MDM2/MDM2-p53 interaction inhibitors, their SAR studies, in silico studies, and the biological efficacy of various inhibitors from natural as well as synthetic origins are also elaborated. An attempt is made to cover recently patented MDM2/MD-M2-p53 interaction inhibitors. � 2023 Bentham Science Publishers.Item Flavonoids as promising anticancer agents: an in silico investigation of ADMET, binding affinity by molecular docking and molecular dynamics simulations(Taylor and Francis Ltd., 2022-09-27T00:00:00) Biharee, Avadh; Yadav, Arpita; Jangid, Kailash; Singh, Yogesh; Kulkarni, Swanand; Sawant, Devesh M.; Kumar, Pradeep; Thareja, Suresh; Jain, Akhlesh KumarCancer is one of the most concerning diseases to humankind. Various treatment strategies are being employed for its treatment, out of which use of natural products is an essential one. Flavonoids have proven to be promising anticancer targets since decades. Also, tubulin is a significant biological target for the development of anticancer agents due to its crucial role in mitosis and abundance throughout the body. In the current study, in silico ADMET parameters of 104 flavonoids were examined, followed by molecular docking with the colchicine binding site of Tubulin protein (PDB; Id 4O2B). The best conformation from each flavonoid subcategory with the best docking score (MolDock score) was further subjected to 100 ns of molecular dynamics to investigate the protein-ligand complex�s stability. Different parameters such as RMSD, RMSF, rGy and SASA were calculated for the six flavonoids using molecular dynamic studies. The top most compound from all the six subcategories of flavonoids elicited best behavior in the colchicine binding site of Tubulin protein. This in silico study employing molecular docking and molecular dynamics simulation provides strong evidence for flavonoids to be excellent anti-tubulin agents for the treatment of cancer. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.Item Selective Estrogen Receptor Modulators (SERMs) for the treatment of ER+ breast cancer: An overview(Elsevier B.V., 2022-08-02T00:00:00) Das, Sweety; Kulkarni, Swanand; Singh, Yogesh; Kumar, Pradeep; Thareja, SureshBreast cancer is a major threat to women's lives throughout the world. Hormone-dependent or estrogen-receptor positive (ER+) breast cancer accounts for more than 80% of all instances. Selective Estrogen Receptor Modulators (SERMs), which specifically control the ERs and limit the progression of breast malignancy, have drawn the interest of researchers in the treatment of breast cancer by regulation of the estrogen receptors (ER), particularly ER?. The mode of action, anti-proliferative potential, SAR, and favourable interactions of the potent candidates are elaborated. Many potent SERMs with diversity in structural space have been rationally designed and reported in the literature for their anti-breast cancer activity. These SERMs exhibited remarkable anti-proliferative activity against ER+ BC. Since, ER? is responsible for the initiation and progression of BC, there is an urgent need to strategically design and synthesize new SERMs, having more selective binding towards ER?. Long term use of traditionally marketed SERMs is associated with several adverse effects, such as development of endometrial cancer and other disorders. Insight of structural features in the present review will prove to be a guideline for the researchers to design and develop potent SERMs for the treatment of ER+ breast cancer. � 2022 Elsevier B.V.