Iodocycloisomerization/Nucleophile Addition Cascade Transformations of 1,2-Alkynediones.

A general electrophilic iodocyclization/nucleophile addition cascade transformation for 1,2-alkynediones for the synthesis of various oxygen heterocycles and access to regioselective alkyne hydroxylation is reported. Furan-tethered ynediones resulted in the construction of exo-enol ethers via carbonyl-alkyne cyclization-initiated heteroarene dearomatization, whereas other (hetero)arene-, alkenyl-, and alkyl-tethered ynediones resulted in the formation of highly functionalized 3(2H)-furanones. Importantly, the developed domino protocols involve the construction of important heterocyclic scaffolds and installation of two functional groups in a single operation. Moreover, the use of water as a nucleophile resulted in regioselective alkyne hydroxylation via furanone ring opening. The developed protocols are characterized by a wide substrate scope, and their utility has been demonstrated by a number of postsynthetic transformations.

Isolation, Structure Elucidation and in Vitro Anticancer Activity of Phytochemical Constituents of Goniothalamus wynaadensis Bedd. and Identification of α-Tubulin as a Putative Molecular Target by in Silico Study.

The phytochemical analysis of ethyl acetate and methanol extract of Goniothalamus wynaadensis Bedd. leaves led to an isolation of eight (1-8) known molecules, among them seven (2-8) isolated for the first time from this species, which includes (+)-goniothalamin oxide (2), goniodiol-7-monoacetate (3), goniodiol-8-monoacetate (4), goniodiol (5), (+)-8-epi-9-deoxygoniopypyrone (6) etc. The phytochemical modification by acetylation of 3 and 4 gave goniodiol diacetate (9) with absolute configuration (6R, 7R, 8R) confirmed by single crystal X-ray diffraction. Compounds 3-9 were cytotoxic against breast, ovarian, prostate and colon cancer cell lines with IC50 <10 µM. Cell cycle analysis and Annexin-V assay on MDA-MB-231 cell using goniodiol-7-monoacetate (3) exhibited apoptotic response as well as necrotic response and showed cell proliferation arrest at G2/M phase. An in silico target identification for these molecules was carried out with an α-tubulin protein target by covalent docking. To gain an in-depth understanding and identify the stability of these protein-ligand complexes on thermodynamic energy levels, further assessment of the isolated molecules binding to the Cys-316 of α-tubulin was performed based on reaction energetic analysis via DFT studies which hinted the isolated molecules may be α-tubulin inhibitors similar to Pironetin. Molecular dynamics reiterated the observations.

Solving the supply of resveratrol tetramers from Papua New Guinean rainforest anisoptera species that inhibit bacterial type III secretion systems.

The supply of (-)-hopeaphenol (1) was achieved via enzymatic biotransformation in order to provide material for preclinical investigation. High-throughput screening of a prefractionated natural product library aimed to identify compounds that inhibit the bacterial virulence type III secretion system (T3SS) identified several fractions derived from two Papua New Guinean Anisoptera species, showing activity against Yersinia pseudotuberculosis outer proteins E and H (YopE and YopH). Bioassay-directed isolation from the leaves of A. thurifera, and similarly A. polyandra, resulted in three known resveratrol tetramers, (-)-hopeaphenol (1), vatalbinoside A (2), and vaticanol B (3). Compounds 1-3 displayed IC50 values of 8.8, 12.5, and 9.9 µM in a luminescent reporter-gene assay (YopE) and IC50 values of 2.9, 4.5, and 3.3 µM in an enzyme-based YopH assay, respectively, which suggested that they could potentially act against the T3SS in Yersinia. The structures of 1-3 were confirmed through a combination of spectrometric, chemical methods, and single-crystal X-ray structure determinations of the natural product 1 and the permethyl ether analogue of 3. The enzymatic hydrolysis of the ß-glycoside 2 to the aglycone 1 was achieved through biotransformation using the endogenous leaf enzymes. This significantly enhanced the yield of the target bioactive natural product from 0.08% to 1.3% and facilitates ADMET studies of (-)-hopeaphenol (1).

Inhibition and kinetic studies of phytochemical constituents of Goniothalamus wynaadensis and their isoxazoline derivatives on α-glucosidase.

α-Glucosidase, an enzyme involved in post-prandial hyperglycaemia, was used as a target to study the effect of compound(s) isolated from Goniothalamus wynaadensis and its isoxazoline derivatives. Among thirteen compounds screened, compounds 1, 3a and 3j exhibited significant inhibition with IC50 values of 63.42, 61.36 and 58.89 µg/mL, respectively, outperforming acarbose (71.72 µg/mL). Kinetic studies revealed competitive binding for compound 1 and uncompetitive/non-competitive binding for 3a and 3j. Fluorescence quenching showed a linear relationship between I0/I at different inhibitor concentrations. The binding sites in α-glucosidase were ≤ 1. The binding constants 3a (0.7307) > 3j (0.6563) > 1 (0.5415) displayed strong interactions. Docking study revealed binding affinities; 3j (-8.9) > 3a (-7.7) > 1 (-7), and acarbose, 1, 3a and 3j had ARG-312, PHE-157 interactions in common to α-glucosidase. The toxicity profile showed compounds fell in classes IV and V. Overall, the results indicate that compounds 1, 3a and 3j are effective against α-glucosidase.

Identification of dual binding mode of Orthodiffenes towards human topoisomerase-I and α-tubulin: exploring the potential role in anti-cancer activity via in silico study.

The drugs prescribed for targeting the tumour growth comprise of chemotherapy regimen involving combinations to cell-cycle phase specific target receptors. The combination therapy with Topoisomerase-I (Topo-I) & anti-tubulin agents are in the clinical trial stages and have scope for identifying new chemical entities with dual binding and inhibiting potential. The checkpoint proteins present at the interface of cell-cycle phases are considered the link between these two that establish the connectivity across the two phases of cell-cycle. In the present study, this potential cross-link or dual targeting is explored via in silico analysis on the natural molecules, Orthodiffene (OD) A-F which are reported from the medicinal plant, Orthosiphon diffusus. These molecules have been reported to possess significant cytotoxicity against Jurkat and HL-60 cancer cells lines in vitro. A detailed in silico analysis on OD-series molecules to evaluate their plausible anticancer mechanism & potential, as well as their in situ ADMET profile study is reported here. The DFT analysis, molecular modelling and molecular dynamics (MD) collectively establishes Topoisomerase-I & α-Tubulin proteins to be the putative target responsible for the cytotoxic activities of OD-B. Orthodiffene series molecules found to be abiding by Lipinksi's rule of 5 for orally bioavailable drug molecule. The present data & study are useful for further exploration of developing new chemical entities based on the structures of OD-series molecules as dual-target inhibitors of Topo-I & tubulin proteins with better efficacies.Communicated by Ramaswamy H. Sarma.

Synthesis, DFT analysis and in-vitro anti-cancer study of novel fused bicyclic pyranone isoxazoline derivatives of Goniodiol-diacetate-a natural product derivative.

Natural products, natural product-inspired molecules and natural product derivatives have contributed around 79% to the new chemotherapies against the most complex, deadly disease, cancer. In this study, a series of novel isoxazoline derivatives of Goniodiol diacetate (fused bicyclic pyranone isoxazoline derivatives)- a natural product derivative, were synthesized with quantitative yield as a single regioisomer by 1,3 - dipolar cycloaddition reaction with different aldoximes. The regiospecific product formed was confirmed by NOESY study and single-crystal X-ray diffraction. The regiospecificity of the product formation was further explained by coefficients of selected atomic orbitals in frontier molecular orbitals and natural population analysis (NPA in eV) of dipolarophile and dipole by density functional theory studies. All the derivatives have demonstrated anti-cancer activity selectively in human breast cancer (MDA-MB-231), ovarian cancer (SKOV3), prostate cancer (PC-3) and colon cancer (HCT-15) cell lines with EC50 < 10 µM. Additionally, Annexin V/PI assay and cell cycle analysis on selected potent compound 3 f exhibited tuned apoptotic response & necrosis compared to standard Vincristine and showed cell growth arrest at the S phase.

Synthesis of antitrypanosomal 1,2-dioxane derivatives based on a natural product scaffold.

A short practical synthesis of a new natural product based scaffold (6), based on antitrypanosomal and antimalarial compounds isolated from different Plakortis species is described. The scaffold contains a peroxide unit that is surprisingly stable to chemical manipulation elsewhere in the molecule, enabling it to be elaborated into a small library of derivatives. It is stable to ozonolysis, reductive work-up with dimethylsulfide and the Wittig reaction with stabilized phosphorus ylides. The scaffold along with its Wittig analogues has displayed low to sub-micro molar (0.2-3.3 µM) antitrypanosomal activity.

Discovery, design and synthesis of Y-shaped peroxisome proliferator-activated receptor δ agonists as potent anti-obesity agents in vivo.

We have discovered and demonstrated the in vitro and in vivo PPARδ-selective activity of novel Y-shaped agonists. These compounds activated hPPARδ with EC(50) values between 1 and 523 nM. Surprisingly, compounds 10a, 11d, 11e and 11f were the most potent and most selective hPPARδ agonists with 10(4)-fold selectivity over the other two subtypes, namely, hPPARα and hPPARγ. The PPARδ ligands 10a, 11e and 11f showed good bioavailability and in vivo efficacy.

An efficient synthesis of 2-benzoxepines from Morita-Baylis-Hillman adducts using heterogeneous recyclable catalysts.

2-Benzoxepines have efficiently been synthesized from Morita-Baylis-Hillman adducts, alkyl 3-aryl-3-hydroxy-2-methylenepropanoates by treatment with HCHO catalyzed by silica supported perchloric acid (HClO4.SiO2) or Amberlyst-15 in CH2Cl2 under reflux for a short period of time (1.5-2.5 h). The catalyst can be recovered and recycled. The antibacterial properties of the new 2-benzoxepines were studied but no activity was found.