Cancer is a significant global health challenge and the second leading cause of death worldwide, responsible for millions of fatalities annually. Despite advances in diagnostics and treatments in cancer, complexities like tumor biology, drug resistance, and toxicity limit its effective management. Herein, we focused on new imidazo-pyridine/pyrazine-fused bicyclic heterocycles. The anticancer potential of the identified bicyclic heterocycles against colorectal cancer (CRC) is established utilizing a multi-faceted approach integrating in silico network pharmacology, ADMET profiling and in vitro cytotoxicity assay. Network pharmacology analysis using the test compounds and CRC cell lines (HCT-116 and CT-26) revealed important molecular targets, such as HSP90AA1, SRC, and PIK3R1 which plays an important role in signaling pathways like PI3K/AKT and MAPK in CRC progression. Gene ontology and KEGG pathway enrichment analyses highlighted the ability of the target compounds to modulate biological processes involved in cell proliferation, apoptosis, and oxidative stress in CRC pathogenesis. ADMET profiling through GastroPlus® demonstrated that these compounds possess favorable pharmacokinetic properties, such as enhanced absorption, bioavailability, and systemic exposure. In vitro cytotoxicity studies on CRC cell lines showed dose-dependent antiproliferative effects. The findings highlight potential of imidazo-pyridine/pyrazine-fused bicyclic heterocycles as promising candidates for treating CRC.

Neuroinflammation is associated with disorders of the nervous system, and it is induced in response to many factors, including pathogen infection, brain injury, toxic substances, and autoimmune diseases. Astrocytes and microglia have critical roles in neuroinflammation. Microglia are innate immune cells in the central nervous system (CNS), which are activated in reaction to neuroinflammation-inducing factors. Astrocytes can have pro- or anti-inflammatory responses, which depend on the type of stimuli presented by the inflamed milieu. Microglia respond and propagate peripheral inflammatory signals within the CNS that cause low-grade inflammation in the brain. The resulting alteration in neuronal activities leads to physiological and behavioral impairment. Consequently, activation, synthesis, and discharge of various pro-inflammatory cytokines and growth factors occur. These events lead to many neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis discussed in this study. After understanding neuroinflammation mechanisms and the involvement of neurotransmitters, this study covers various drugs used to treat and manage these neurodegenerative illnesses. The study can be helpful in discovering new drug molecules for treating neurodegenerative disorders.

Background: Resveratrol, a natural polyphenol product, is used in plant defense from fungal and microbial aggression. It is found naturally, especially in plants such as grapes, peanuts, and berries. It has the highest concentrations in blueberries, mulberries, blackberries, and the skin of red grapes. Resveratrol has various pharmacological properties such as anti-inflammatory, cytoprotective, and antineoplastic activities. Methods: We conducted a literature survey using standard tools such as Google, Reaxys, Scifinder, Scihub, and patent Espacenet to compile the biosynthetic pathways, all organic synthetic methods, and biological activities reported for resveratrol till date. Results: More than one hundred research articles and patents were referred to write this review. About twenty-five of them are related to chemical synthesis, and the rests are about the source, pharmacological activity, and other properties of resveratrol. This study reveals that many common pathways are involved in various pharmacological activities, which can be useful for treating various diseases based on the pathways involved. Reactions such as Pfitzner-Moffatt oxidation, Wittig-Horner condensation, Mizoroki-Heck, Perkin, Wittig, etc. have been used in resveratrol synthesis. A structure-activity relationship was also established based on its analogs and derivatives. Conclusion: This review examined and reported all the published biological activities and chemical syntheses of resveratrol apart from the biosynthetic pathway. Due to its valuable biological activities, various synthetic approaches have been reported till date. The reported synthetic operations are suitable for large-scale industrial production. Moreover, these comprehensive synthetic procedures could be utilized in the preparation of stilbenes and other related compounds in future endeavors.

A series of beta-carboline derivatives was synthesized by the Pictet-Spengler reaction with or without the combretastatin skeleton. The structures of these derivatives were elucidated by spectroscopic techniques. All synthesized compounds were evaluated for their anti-inflammatory activity in human neutrophils. Among them, two compounds, NTU-228 and HK-72, showed significant inhibitory effects on N-formyl-Met-Leu-Phe (fMLF)-induced superoxide anion generation in human neutrophils with IC50 values of 5.58 +/- 0.56 and 2.81 +/- 0.07 mu M, respectively. Neither NTU-228 nor HK-72 caused cytotoxicity in human neutrophils. NTU-228 inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and intracellular Ca2+ levels ([Ca2+](i)) in fMLF-activated human neutrophils. Additionally, HK-72 selectively inhibited the fMLF-induced phosphorylation of p38 and [Ca2+](i) in human neutrophils. Molecular docking analysis showed a favorable binding affinity of HK-72 toward p38 MAPK. The proposed synthetic strategy opens up new opportunities for the synthesis of novel potential candidates against neutrophilic inflammation.

Octocoral Sinularia leptoclados has been identified as a source of bioactive 9,11-secosteroids. This study adopted a targeted isolation approach to the discovery and analysis of five 9,11-secosteroids, including two novel compounds named sinleptosterols A (1) and B (2) as well as five known analogues (8αH-3β,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9-one (3), 8βH-3β,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9-one (4), leptosterol A (5), (24S)-3β,11-dihydroxy-24-methyl-9,11-secocholest-5-en-9-one (6), and 3β,11-dihydroxy-9,11-secogorgost-5-en-9-one (7)) in terms of 1H-NMR patterns and potency against neutrophilic inflammation. The structure of secosteroids 1 and 2 was deduced from general spectroscopic analysis and an examination of NMR spectra. Among the above-mentioned isolates, compound 4 had the most pronounced effect in inhibiting elastase release and superoxide anion generation, with the IC50 values of 2.96 and 1.63 μM, respectively.

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.

A series of 3-aroylindole hydroxamic acids (10-17) were developed based on the concept of a structural combination of tubulin and histone deacetylase (HDAC) inhibitors. This was accomplished by introducing hydroxamic acid-containing moieties at the N1 position of the tubulin assembly inhibitor, compound 9 (SCB01A, BPROL075, phase II trial). Most of synthetic compounds produced in this way displayed comparable HDAC inhibitory activity, and four (10, 12-14) of them also inhibit tubulin assembly. Notably, compound 12 possesses not only tubulin and HDAC inhibitory activity but also shows HDAC6 selectivity over other HDAC isoforms. In addition, it exhibits remarkable inhibitory activity against the growth cancer cells in vitro and in vivo (PC3 and RPMI-8226 cells). Notably, it suppresses the growth of multiple myeloma xenografts without leading to the death of teated animals like reference compound. In sum, this study provided potential compounds with safer profiles for cancer treatment. (C) 2016 Elsevier Masson SAS. All rights reserved.

Glycosylated stilbenes are biologically active secondary metabolites of plants and have the potential to alleviate a broad range of human diseases. However, some of these compounds are not naturally abundant, and thus the synthesis of such molecules is desirable. This paper reports the first synthesis of oxyresveratrol 2-O-β-d-glucopyranoside (1) and 2,3,5,4'-tetrahydroxystilbene 2-O-β-d-glucopyranoside (1'), which are stilbene glycosides obtained from the rhizomes of Schoenocaulon officinale and Polygonum multiflorum, respectively. A facile four-step synthesis of 1 involved selective protection of the hydroxy groups and Wittig olefination to generate the compound in 8% overall yield. For compound 1', a 10-step synthesis utilized selective protection of the hydroxy groups, Baeyer-Villiger oxidation, modified Duff formylation, and Wittig olefination to generate the compound in 6.9% overall yield.

Background: HDAC inhibition is known to modulate expression of tumour suppressor genes and induce cell differentiation, growth arrest and apoptosis. The aim of this study was to evaluate the efficacy of a novel series of hydroxamic acid based HDAC inhibitors in cell based assays and tumour xenograft models. Material and Methods: A series of novel hydroxamate derivatives were synthesized and evaluated. HDAC enzyme inhibitory activity was measured using Hela nuclear extracts. Anti-proliferative activity was assessed in a panel of cancer cell lines. Anti-apoptotic activity was evaluated by caspase-3 activation. In vivo efficacy was evaluated in lung adenocarcinoma xenograft model. Results: The compounds showed potent HDAC inhibitory activity and anti-proliferative activity in several cancer cell lines. In an in vivo A549 lung xenograft model, the compounds exhibited significant tumor growth inhibition. Conclusion: The novel HDAC inhibitors showed anti-proliferative activity against several human cancer cell lines and also anti-tumor activity in a Mouse xenograft model.

This study reports the synthesis of a series of 2-aroylquinoline-5,8-diones (11–23) on the basis of scaffold hopping.

HDAC inhibition is emerging as a new strategy for cancer therapy. We previously reported that Nhydroxy- 3-{4-[2-(2-methyl-1H-indol-3-yl)-ethylsulfamoyl]-phenyl}-acrylamide (9) demonstrated potent histone deacetylases (HDAC) inhibition and anti-inflammatory effects. This continuous study provides detailed structureactivity relationship (SAR) of novel indol-3-ethylsulfamoylphenylacrylamides as anti-cancer agents. These compounds are endowed with potent HDAC inhibitory activity, almost 2.5 folds to 42 folds better than suberanilohydroxamic acid (SAHA). Compounds 8, 10, 11 and 17 exhibited significant inhibitory effects on various cancer cell lines with GI50 values in the range of 0.02 to 0.35 μM which are 10-50 folds better than SAHA. In-vivo nude mice model indicated the anti-angiogenic potential of these acrylamides. This study has indicated the potential of 3-{4-[2-(1-Ethyl-2-methyl-1H-indol-3-yl)-ethyl-N-tert-butoxycarbonylsulfamoyl]-phenyl}-N-hydroxy-acrylamide (11, mean GI50 = 0.04 μM) as a lead molecule for further development as anti-cancer agent.

This study reports the design and synthesis of 2-(phenylsulfonyl)quinoline N-hydroxyacrylamides (8a-k). Structure-activity relationship studies focusing on regio-effect of N-hydroxyacrylamide moiety and influence of the sulfonyl linker revealed that N-hydroxy-3-[3-(quinoline-2-sulfonyl)-phenyl]-acrylamide (8f) showed remarkable enzymatic and cellular activity. The GI(50) values of 8f for HL-60, HCT116, PC-3, and A549 cells were found to be 0.29, 0.08, 0.15, and 0.27 mu M, respectively. The compounds are therefore more potent than FDA approved PXD-101 and SAHA. They also have an effect on the acetylation degree of histone H3 and alpha-tubulin. In in vivo studies, 8f showed marked inhibition of the growth of HCT116 xenografts. (C) 2016 Published by Elsevier Masson SAS.

Plant-derived compounds have played very crucial role in the field of anti-cancer drugs. Various important anti-cancer agents like vincristine, vinblastin, camptothecin, paclitaxel and podophyllotoxin have been isolated from the various plant source. Most of the anticancer drugs act on tubulin site. Beauty of these drugs is planar structure because space between a & ß-subunit of tubulin is very less and planar compounds can fit in the gap and bind to ß-Subunit. Several new agents have been found against cancer including combretastatin A4 phosphate, aliphatic esters and lignans. The basic aim of this review is to explore the potential of newly discovered anticancer compounds, from natural resourses, as a lead for anticancer drug development.

A total synthesis of denbinobin (1) in seven steps with an overall yield of 10% is reported. This synthesis used an FeCl3-assisted cyclization of stilbene to form a phenanthrene. The poor yields of the decarboxylation and methoxylation steps were improved upon to become essentially quantitative. This scalable methodology was carried out using ordinary laboratory reagents.

This study reports the design and synthesis of 2-( phenylsulfonyl)quinoline N-hydroxyacrylamides ( 8a-k). Structure-activity relationship studies focusing on regio-effect of N-hydroxyacrylamide moiety and influence of the sulf onyl linker revealed that N-hydroxy-3-[3-(quinoline-2-sulfonyl)-phenyl]-acryla mide (8f) showed remarkable enzymatic and cellular activity. The GI 50 values of 8f for HL-60, HCT116, PC-3, and A549 cells were found to be 0.29, 0.08, 0.15, and 0.27 μM, respectively. The compounds are therefore more p t nt than FDA approved PXD-101 and SAHA. They also have an effect on the acetylation degree of histone H3 and α-tubulin. In in vivo studies, 8f showed marked inhibition of the growth of HCT116 x enografts.

OBJECTIVE:In this study, the anticancer mechanisms of MT-4 were examined in A2780 and multidrug-resistant NCI-ADR/res human ovarian cancer cell lines.METHODS:To evaluate the activity of MT-4, we performed in vitro cell viability and cell cycle assays and in vivo xenograft assays. Immunoblotting analysis was carried out to evaluate the effect of MT-4 on ovarian cancer. Tubulin polymerization was determined using a tubulin binding assay.RESULTS:MT-4 (2-Methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-ethyl]-phenol), a derivative of moscatilin, can inhibit both sensitive A2780 and multidrug-resistant NCI-ADR/res cell growth and viability. MT-4 inhibited tubulin polymerization to induce G2/M arrest followed by caspase-mediated apoptosis. Further studies indicated that MT-4 is not a substrate of P-glycoprotein (p-gp). MT-4 also caused G2/M cell cycle arrest, accompanied by the upregulation of cyclin B, p-Thr161 Cdc2/p34, polo-like kinase 1 (PLK1), Aurora kinase B, and phospho-Ser10-histone H3 protein levels. In addition, we found that p38 MAPK pathway activation was involved in MT-4-induced apoptosis. Most importantly, MT-4 also decreased heat shock protein 27 expression and reduced its interaction with caspase-3, which inured cancer cells to chemotherapy resistance. Treatment of cells with SB203580 or overexpression of dominant negative (DN)-p38 or wild-type HSP27 reduced PARP cleavage caused by MT-4. MT-4 induced apoptosis through regulation of p38 and HSP27. Our xenograft models also show the in vivo efficacy of MT-4. MT-4 inhibited both A2780 and NCI-ADR/res cell growth in vitro and in vivo.CONCLUSION:These findings indicate that MT-4 could be a potential lead compound for the treatment of multidrug-resistant ovarian cancer.

Protein kinases constitute one of the largest and most functionally diverse gene families that regulate key cell functions. In past several years, kinase inhibition has emerged as potential anti-cancer drug target. Purine is a priveleged heterocyclic nucleus which exists in the chemical architecture of various bioactive compounds. Numerous reports on the use of purine analogues in the treatment of acute leukemias (thiopurines, pentostatin), as antiviral (acyclovir, penciclovir, ganciclovir), as immunosuppressive (azathioprine), as antitumor (vidarabine), as bronchodilator (theophylline) have been revealed. In the past decade, purine analogues have emerged as significantly potent kinase inhibitors. A fair amount of research has been done and several patents have also been published highlighting the kinase inhibitory action of purines. Caffeine, 2-aminopurine, purvalanol-A, seleciclib, FSBA, adenosine thiol analogue possessing purine as the basic moiety fall under this category. In view of the use of purines for the inhibition of kinases, there is need for compilation of data specifying the prominence of purines in the treatment of cancer through this mechanism. The structure of the potent compounds, their IC50 values, models used and the enzymes/ receptors/ targets involved have been presented in this review. The present compilation covers the patents published entailing the purines as kinase inhibitors and the purine drugs employed in chemotherapy.

Molecular hybridization (MH) is a strategy of rational design of such ligands or prototypes based on the recognition of pharmacophoric sub-units in the molecular structure of two or more known bioactive derivatives which, through the adequate fusion of these sub-units, lead to the design of new hybrid architectures that maintain pre-selected characteristics of the original templates. The concept of molecular hybridization and the promises/challenges associated with these hybrid molecules along with recent advances in anticancer hybrids and critical discussions on the future aspects of the hybrid drugs have already been presented through number of reports. However, this chapter presents the structures of potent hybrids reported during the last two decades along with a detailed account of the patent literature from the year 1990 to 2014. Significant number of patents on the molecules designed through this valuable drug design technique clearly highlight the present focus of the researchers all around the globe towards hybrid molecules capable of amplifying the effect of individual functionalities through action on another bio target or to interact with multiple targets as one single molecule lowering the risk of drug-drug interactions and minimizing the drug resistance.

Background: Crotepoxide is a potent molecule for the development of anticancer pharmacodynamics therefore; estimation process for such novel compound is highly desired for future research work in the field of natural products.Introduction: Piper attenuatum is an important species used as a drug in Ayurvedic system of medicine. Pipoxide chlorohydrin, galbelgin, 8-hentriacontanol, several aristolactams, and 4,5-dioxaporphines are the main chemical constituents reported from this plant.Method: Methods based on HPTLC and HPLC with PDA detector for rapid quantitative estimation of crotepoxide in the methanolic extract of Piper attenuatum fruits has been described.Result: The linearity for crotepoxide was found to be in the concentration range of 0.2 to 1.2 mu g/spot with coefficient of determination 0.9988 for HPTLC and 1 to 32 mu g/mL with coefficient of determination 0.9990 for HPLC with respect to peak area. Limit of detection (LOD) and limit of quantification (LOQ) were found to be 60 ng/spot and 198 ng/spot, for HPTLC and 15 ng/mL and 50 ng/mL for HPLC, respectively. Repeatability studies have shown 0.14 % RSD and SE 2.06 for HPTLC and 0.65 % RSD for HPLC. Recovery values of 96.06 to 103.02 % for HPTLC and 98.05 to 100.09 % for HPLC indicate excellent accuracy of the methods.Conclusion: HPTLC and HPLC analyses of the fruit extract had shown percent content of crotepoxide 2.5 and 2.43, respectively, which appears to be the highest from any plant source. The developed methods are accurate, precise, cost-effective, and can be successfully applied for the estimation of crotepoxide.