Small molecule tractable PARP inhibitors: Scaffold construction approaches, mechanistic insights and structure activity relationship.

Diverse drug design strategies viz. molecular hybridization, substituent installation, scaffold hopping, isosteric replacement, high-throughput screening, induction and separation of chirality, structure modifications of phytoconstituents and use of structural templates have been exhaustively leveraged in the last decade to load the chemical toolbox of PARP inhibitors. Resultantly, numerous promising scaffolds have been pinpointed that in turn have led to the resuscitation of the credence to PARP inhibitors as cancer therapeutics. This review briefly presents the physiological functions of PARPs, the pharmacokinetics, and pharmacodynamics, and the interaction profiles of FDA-approved PARP inhibitors. Comprehensively covered is the section on the drug design strategies employed by drug discovery enthusiasts for furnishing PARP inhibitors. The impact of structural variations in the template of designed scaffolds on enzymatic and cellular activity (structure-activity relationship studies) has been discussed. The insights gained through the biological evaluation such as profiling of physicochemical properties andin vitroADME properties, PK assessments, and high-dose pharmacology are covered.

Flavone-based dual PARP-Tubulin inhibitor manifesting efficacy against endometrial cancer.

Structural tailoring of the flavone framework (position 7) via organopalladium-catalyzed C-C bond formation was attempted in this study. The impact of substituents with varied electronic effects (phenyl ring, position 2 of the benzopyran scaffold) on the antitumor properties was also assessed. Resultantly, the efforts yielded a furyl arm bearing benzopyran possessing a 4-fluoro phenyl ring (position 2) (14) that manifested a magnificent antitumor profile against the Ishikawa cell lines mediated through dual inhibition of PARP and tubulin [(IC50 (PARP1) = 74 nM, IC50 (PARP2) = 109 nM) and tubulin (IC50 = 1.4 µM)]. Further investigations confirmed the ability of 14 to induce apoptosis as well as autophagy and cause cell cycle arrest at the G2/M phase. Overall, the outcome of the study culminated in a tractable dual PARP-tubulin inhibitor endowed with an impressive activity profile against endometrial cancer.

Beyond the vaccines: a glance at the small molecule and peptide-based anti-COVID19 arsenal.

Unprecedented efforts of the researchers have been witnessed in the recent past towards the development of vaccine platforms for the control of the COVID-19 pandemic. Albeit, vaccination stands as a practical strategy to prevent SARS-CoV-2 infection, supplementing the anti-COVID19 arsenal with therapeutic options such as small molecules/peptides and antibodies is being conceived as a prudent strategy to tackle the emerging SARS-CoV-2 variants. Noteworthy to mention that collective efforts from numerous teams have led to the generation of a voluminous library composed of chemically and mechanistically diverse small molecules as anti-COVID19 scaffolds. This review article presents an overview of medicinal chemistry campaigns and drug repurposing programs that culminated in the identification of a plethora of small molecule-based anti-COVID19 drugs mediating their antiviral effects through inhibition of proteases, S protein, RdRp, ACE2, TMPRSS2, cathepsin and other targets. In light of the evidence ascertaining the potential of small molecule drugs to approach conserved proteins required for the viral replication of all coronaviruses, accelerated FDA approvals are anticipated for small molecules for the treatment of COVID19 shortly. Though the recent attempts invested in this direction in pursuit of enrichment of the anti-COVID-19 armoury (chemical tools) are praiseworthy, some strategies need to be implemented to extract conclusive benefits of the recently reported small molecule viz. (i) detailed preclinical investigation of the generated anti-COVID19 scaffolds (ii) in-vitro profiling of the inhibitors against the emerging SARS-CoV-2 variants (iii) development of assays enabling rapid screening of the libraries of anti-COVID19 scaffold (iv) leveraging the applications of machine learning based predictive models to expedite the anti-COVID19 drug discovery campaign (v) design of antibody-drug conjugates.

Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends.

Epigenetic drug discovery field has evidenced significant advancement in the recent times. A plethora of small molecule inhibitors have progressed to clinical stage investigations and are being explored exhaustively to ascertain conclusive benefits in diverse malignancies. Literature precedents indicates that substantial amount of efforts were directed towards the use of epigenetic tools in monotherapy as well as in combination regimens at the clinical level, however, the preclinical/preliminary explorations were inclined towards the identification of prudent approaches that can leverage the anticancer potential of small molecule epigenetic inhibitors as single agents only. This review article presents an update of FDA approved epigenetic drugs along with the epigenetic inhibitors undergoing clinical stage investigations in different cancer types. A detailed discussion of the pragmatic strategies that are expected to steer the progress of the epigenetic therapy through the implementation of emerging approaches such as PROTACS and CRISPR/Cas9 along with logical ways for scaffold fabrication to selectively approach the enzyme isoforms in pursuit of garnering amplified antitumor effects has been covered. In addition, the compilation also presents the rational strategies for the construction of multi-targeting scaffold assemblages employing previously identified pharmacophores as potential alternatives to the combination therapy.

The HDAC/HSP90 Inhibitor G570 Attenuated Blue Light-Induced Cell Migration in RPE Cells and Neovascularization in Mice through Decreased VEGF Production.

Age-related macular degeneration (AMD) occurs due to an abnormality of retinal pigment epithelium (RPE) cells that leads to gradual degeneration of the macula. Currently, AMD drug pipelines are endowed with limited options, and anti-VEGF agents stand as the dominantly employed therapy. Despite the proven efficacy of such agents, the evidenced side effects associated with their use underscore the need to elucidate other mechanisms involved and identify additional molecular targets for the sake of therapy improvement. The previous literature provided us with a solid rationale to preliminarily explore the potential of selective HDAC6 and HSP90 inhibitors to treat wet AMD. Rather than furnishing single-target agents (either HDAC6 or HSP90 inhibitor), this study recruited scaffolds endowed with the ability to concomitantly modulate both targets (HDAC6 and HSP90) for exploration. This plan was anticipated to accomplish the important goal of extracting amplified benefits via dual inhibition (HDAC6/HSP90) in wet AMD. As a result, G570 (indoline-based hydroxamate), a dual selective HDAC6-HSP90 inhibitor exerting its effects at micromolar concentrations, was pinpointed in the present endeavor to attenuate blue light-induced cell migration and retinal neovascularization by inhibiting VEGF production. In addition to the identification of a potential chemical tool (G570), the outcome of this study validates the candidate HDAC6-HSP90 as a compelling target for the development of futuristic therapeutics for wet AMD.

Steering the antitumor drug discovery campaign towards structurally diverse indolines.

Indoline framework is often perpended as a privileged heterocycle present in medicinally valuable compounds of natural and synthetic origin. This review article presents the rational approaches/strategies employed for the design of anticancer indolines along with the structure activity relationship and mechanistic insights revealed in the in-vitro and in-vivo assays. The chemist has always been fascinated towards the indoline ring for the construction of antitumor scaffolds owing to its versatility as evidenced by its existence in scaffolds inducing antiproliferative effects via diverse mechanisms. To the delight of medicinal chemist, the applicability of indoline has also been expanded towards the design of dual inhibitors (multitargeting anticancer agents) as well as PROTACS. Overall, it can be concluded that indoline moiety is a magic bullet and the scaffolds containing this ring are foraying towards detailed preclinical and clinical stage investigations by leaps and bounds.

Amide-tethered quinoline-resorcinol conjugates as a new class of HSP90 inhibitors suppressing the growth of prostate cancer cells.

The study is focused on the design and synthesis of amide tethered quinoline-resorcinol hybrid constructs as a new class of HSP90 inhibitor. In-vitro studies of the synthetic compounds led to the identification of compound 11, which possesses potent cell growth inhibitory effects against HCT116, Hep3B and PC-3 cell lines, exerted through HSP90 inhibition. Compound 11 triggers degradation of HSP90 client proteins along with concomitant induction of HSP70, demonstrates apoptosis inducing ability and causes G2M phase cell cycle arrest in PC-3 cells. Molecular modeling was used to dock compound 11 into the HSP90 active site and key interactions with the amino acid residues of the HSP90 chaperone protein were determined.

Correction: 2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition.

Correction for '2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition' by Kunal Nepali et al., Org. Biomol. Chem., 2016, 14, 716-723.

Triazole tethered isatin-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies.

In an attempt to develop potent anti-tubulin agents against most dreadful disease cancer, a library of 28 novel triazole tethered isatin-coumarin hybrids were synthesized by click chemistry approach. Synthesized hybrids were characterized and evaluated against a panel of human cancer cell lines viz. THP-1, COLO-205, HCT-116 and PC-3. Biological assay unveiled that, compounds A-1 to A-6, B-1 to B-4 and C-1 to C-3 displayed significant inhibitory potential against THP-1, COLO-205 and HCT-116 cell lines which were more sensitive towards the designed hybrids. PC-3 among these cell lines was found to be almost resistant. Established SAR revealed marked dependence of the cytotoxic activity on the type of substituent on isatin and the length of carbon-bridge connecting isatin moiety with triazole ring. Unsubstituted isatin and two carbon-bridge were found to be crucial for cytotoxicity. Three most potent hybrids (A-1, A-2 and B-1) were further tested for tubulin polymerization inhibition. Among these three compounds, A-1 found to be endowed with most prominent tubulin polymerization inhibition potential with IC50 value of 1.06µM which was further confirmed by using confocal microscopy. Possible binding interactions between the most potent hybrid molecule A-1 and tubulin were also divulged by molecular modeling studies.

Benzoflavones as cholesterol esterase inhibitors: Synthesis, biological evaluation and docking studies.

A library of forty 7,8-benzoflavone derivatives was synthesized and evaluated for their inhibitory potential against cholesterol esterase (CEase). Among all the synthesized compounds seven benzoflavone derivatives (A-7, A-8, A-10, A-11, A-12, A-13, A-15) exhibited significant inhibition against CEase in in vitro enzymatic assay. Compound A-12 showed the most promising activity with IC50 value of 0.78nM against cholesterol esterase. Enzyme kinetic studies carried out for A-12, revealed its mixed-type inhibition approach. Molecular protein-ligand docking studies were also performed to figure out the key binding interactions of A-12 with the amino acid residues of the enzyme's active site. The A-12 fits well at the catalytic site and is stabilized by hydrophobic interactions. It completely blocks the catalytic assembly of CEase and prevents it to participate in ester hydrolysis mechanism. The favorable binding conformation of A-12 suggests its prevailing role as CEase inhibitor.

2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition.

This study reports the synthesis of a series of 2-aroylquinoline-5,8-diones (11-23) on the basis of scaffold hopping. The presence of a methoxy group at C6 assists the highly regioselective incorporation with various amines, and simplifies the structural identification process. Among the synthetic compounds, 6-dimethylamino-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (12) and 7-pyrrolidin-1-yl-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (23) exhibit remarkable anti-proliferative activity against the cancer cell lines tested with mean IC50 values of 0.14 and 0.27 µM, respectively. Compound 23 showed moderate inhibitory activity against tubulin polymerization with an IC50 value of 5.9 µM. In a western blot analysis, 23 caused induction of HSP70 and degradation of Akt, revealing that it possesses HSP90 inhibitory activity.

Microwave assisted synthesis of naphthopyrans catalysed by silica supported fluoroboric acid as a new class of non purine xanthine oxidase inhibitors.

A series of naphthopyrans was synthesized employing silica supported fluoroboric acid under solvent free conditions in a microwave reactor. The catalytic influence of HBF4-SiO2 was investigated in detail to optimize the reaction conditions. The synthesised compounds were evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Structure-activity relationship analyses have also been presented. Among the synthesised compounds, NP-17, NP-19, NP-20, NP-23, NP-24, NP-25 and NP-26 were the active inhibitors with an IC50 ranging from 4 to 17 µM. Compound NP-19 with a thiophenyl ring at position 1 emerged as the most potent xanthine oxidase inhibitor (IC50=4 µM) in comparison to allopurinol (IC50=11.10 µM) and febuxostat (IC50=0.025 µM). The basis of significant inhibition of xanthine oxidase by NP-19 was rationalized by its molecular docking at MTE binding site of xanthine oxidase.

Synthesis and evaluation of naphthoflavones as a new class of non purine xanthine oxidase inhibitors.

In view of reported xanthine oxidase inhibitory potential of naphthopyrans and flavones, naphthoflavones as hybrids of the two were designed, synthesized and evaluated for in vitro xanthine oxidase inhibitory activity in the present study. The results of the assay revealed that the naphthoflavones possess promising inhibitory potential against the enzyme with IC50 values ranging from 0.62 to 41.2 µM. Structure activity relationship indicated that the nature and placement of substituents on the phenyl ring at 2nd position remarkably influences the inhibitory activity. Substitution of halo and nitro groups at ortho and para position of the phenyl ring (2nd position) remarkably favored the activity. NF-4 with p-fluoro phenyl ring was the most potent inhibitor with IC50 value of 0.62 µM. Enzyme kinetics study was also performed to investigate the inhibition mechanism and it was found that the naphthoflavones displayed mixed type inhibition. The basis of significant inhibition of xanthine oxidase by NF-4 was rationalized by molecular modeling studies.

Design, synthesis and evaluation of 2,4-diarylpyrano[3,2-c]chromen-5(4H)-one as a new class of non-purine xanthine oxidase inhibitors.

Abstract Keeping in view the recent success of molecular hybridization technique in drug design, 2,4-diarylpyrano[3,2-c]chromen-5(4H)-ones as conjugates of coumarins and chalcones have been designed and synthesized in the present study. The catalytic efficiency of various Lewis acids for the synthesis of designed conjugates under neat conditions was investigated, and SiO2 (200-400 mesh)-ZnCl2 was optimized as the best catalyst among the tested ones. The conjugates were evaluated for in-vitro xanthine oxidase activity. The results of the in-vitro assay were quite promising as some conjugates were endowed with remarkable inhibitory potential against the enzyme. HV-8, 11 and 12 were found to be high-potent inhibitors with HV-11 (the most potent inhibitor) possessing an IC50 value of 2.21 µM. The most active conjugate HV-11 was evaluated for the type of inhibition and was found to be a mixed type inhibitor. The compliance of some selected conjugates to the Lipinski rule was also calculated.

4,6-Diaryl/heteroarylpyrimidin-2(1H)-ones as a new class of xanthine oxidase inhibitors.

A series of 4,6-diaryl/heteroarylpyrimidones was synthesized employing silica-supported fluoroboric acid under solvent-free conditions in a microwave reactor. The catalytic influence of HBF4-SiO2 was investigated in detail to optimize the reaction conditions. The synthesized compounds were evaluated for in vitro xanthine oxidase (XO) inhibitory activity for the first time. Structure-activity relationship analyses are also presented. Among the synthesized compounds, VA-5, -9, -10, -12, -22, -23, and -25 were the active inhibitors with IC50 values ranging from 6.45 to 13.46 µM. Compound VA-25 with a pyridinyl ring as ring A and a thiophenyl ring as ring B emerged as the most potent XO inhibitor (IC50 = 6.45 µM) in comparison to allopurinol (IC50 = 12.24 µM). Some of the important interactions of VA-25 with the amino acid residues of the active site of XO were figured out by molecular modeling studies.

Spleen tyrosine kinase (SYK): an emerging target for the assemblage of small molecule antitumor agents.

INTRODUCTION: Spleen tyrosine kinase (SYK), a nonreceptor tyrosine kinase, has emerged as a vital component in the complex symphony of cancer cell survival and division. SYK activation (constitutive) is documented in various B-cell malignancies, and its inhibition induces programmed cell death. In some instances, it also acts as a tumor suppressor. AREAS COVERED: Involvement of the SYK in the cancer growth, specifically in the progression of chronic lymphocytic leukemia (CLL), diffuse large B cell lymphomas (DLBCLs), acute myeloid leukemia (AML), and multiple myeloma (MM) is discussed. Therapeutic strategies to target SYK in cancer, including investigational SYK inhibitors, combinations of SYK inhibitors with other drugs targeting therapeutically relevant targets, and recent advancements in constructing new structural assemblages as SYK inhibitors, are also covered. EXPERT OPINION: The SYK inhibitor field is currently marred by the poor translation rate of SYK inhibitors from preclinical to clinical studies. Also, dose-limited toxicities associated with the applications of SYK inhibitors have been evidenced. Thus, the development of new SYK inhibitory structural templates is in the need of the hour. To accomplish the aforementioned, interdisciplinary teams should incessantly invest efforts to expand the size of the armory of SYK inhibitors.

Recent advances and future directions on small molecule VEGFR inhibitors in oncological conditions.

"A journey of mixed emotions" is a quote that best describes the progress chart of vascular endothelial growth factor receptor (VEGFR) inhibitors as cancer therapeutics in the last decade. Exhilarated with the Food and Drug Administration (FDA) approvals of numerous VEGFR inhibitors coupled with the annoyance of encountering the complications associated with their use, drug discovery enthusiasts are on their toes with an unswerving determination to enhance the rate of translation of VEGFR inhibitors from preclinical to clinical stage. The recently crafted armory of VEGFR inhibitors is a testament to their growing dominance over other antiangiogenic therapies for cancer treatment. This review perspicuously underscores the earnest attempts of the researchers to extract the antiproliferative potential of VEGFR inhibitors through the design of mechanistically diverse structural assemblages. Moreover, this review encompasses sections on structural/molecular properties and physiological functions of VEGFR, FDA-approved VEGFR inhibitors, and hurdles restricting the activity range/clinical applicability of VEGFR targeting antitumor agents. In addition, tactics to overcome the limitations of VEGFR inhibitors are discussed. A clear-cut viewpoint transmitted through this compilation can provide practical directions to push the cart of VEGFR inhibitors to advanced-stage clinical investigations in diverse malignancies.

Leveraging a rationally designed veliparib-based anilide eliciting anti-leukemic effects for the design of pH-responsive polymer nanoformulation.

Careful recruitment of the components of the HDAC inhibitory template culminated in veliparib-based anilide 8 that elicited remarkable cell growth inhibitory effects against HL-60 cell lines mediated via dual modulation of PARP [(IC50 (PARP1) = 0.02 nM) and IC50 (PARP2) = 1 nM)] and HDACs (IC50 value = 0.05, 0.147 and 0.393 µM (HDAC1, 2 and 3). Compound 8 downregulated the expression levels of signatory biomarkers of PARP and HDAC inhibition. Also, compound 8 arrested the cell cycle at the G0/G1 phase and induced autophagy. Polymer nanoformulation (mPEG-PCl copolymeric micelles loaded with compound 8) was prepared by the nanoprecipitation technique. The mPEG-PCL diblock copolymer was prepared by ring-opening polymerization method using stannous octoate as a catalyst. The morphology of the compound 8@mPEG-PCL was examined using TEM and the substance was determined to be monodispersed, spherical in form, and had an average diameter of 138 nm. The polymer nanoformulation manifested pH-sensitive behaviour as a greater release of compound 8 was observed at 6.2 pH as compared to 7.4 pH mimicking physiological settings. The aforementioned findings indicate that the acidic pH of the tumour microenvironment might stimulate the nanomedicine release which in turn can attenuate the off-target effects precedentially claimed to be associated with HDAC inhibitors.

First-in-Class Dual EZH2-HSP90 Inhibitor Eliciting Striking Antiglioblastoma Activity In Vitro and In Vivo.

Structural analysis of tazemetostat, an FDA-approved EZH2 inhibitor, led us to pinpoint a suitable site for appendage with a pharmacophoric fragment of second-generation HSP90 inhibitors. Resultantly, a magnificent dual EZH2/HSP90 inhibitor was pinpointed that exerted striking cell growth inhibitory efficacy against TMZ-resistant Glioblastoma (GBM) cell lines. Exhaustive explorations of chemical probe 7 led to several revelations such as (i) compound 7 increased apoptosis/necrosis-related gene expression, whereas decreased M phase/kinetochore/spindle-related gene expression as well as CENPs protein expression in Pt3R cells; (ii) dual inhibitor 7 induced cell cycle arrest at the M phase; (iii) compound 7 suppressed reactive oxygen species (ROS) catabolism pathway, causing the death of TMZ-resistant GBM cells; and (iv) compound 7 elicited substantial in vivo anti-GBM efficacy in experimental mice xenografted with TMZ-resistant Pt3R cells. Collectively, the study results confirm the potential of dual EZH2-HSP90 inhibitor 7 as a tractable anti-GBM agent.

Dual inhibition of CYP17A1 and HDAC6 by abiraterone-installed hydroxamic acid overcomes temozolomide resistance in glioblastoma through inducing DNA damage and oxidative stress.

Glioblastoma (GBM) is a highly aggressive and treatment-resistant brain tumor, necessitating novel therapeutic strategies. In this study, we present a mechanistic breakthrough by designing and evaluating a series of abiraterone-installed hydroxamic acids as potential dual inhibitors of CYP17A1 and HDAC6 for GBM treatment. We established the correlation of CYP17A1/HDAC6 overexpression with tumor recurrence and temozolomide resistance in GBM patients. Compound 12, a dual inhibitor, demonstrated significant anti-GBM activity in vitro, particularly against TMZ-resistant cell lines. Mechanistically, compound 12 induced apoptosis, suppressed recurrence-associated genes, induced oxidative stress and initiated DNA damage response. Furthermore, molecular modeling studies confirmed its potent inhibitory activity against CYP17A1 and HDAC6. In vivo studies revealed that compound 12 effectively suppressed tumor growth in xenograft and orthotopic mouse models without inducing significant adverse effects. These findings highlight the potential of dual CYP17A1 and HDAC6 inhibition as a promising strategy for overcoming treatment resistance in GBM and offer new hope for improved therapeutic outcomes.