Integrasone Derivatives Isolated from Lepteutypa sp. KT4162 and Their Anti-HIV-1 Integrase Activity.

Five integrasone derivatives, integrasone C (1), isointegrasone C (2), integrasone D1 (3), integrasone D2 (4), and integrasone E (5), were isolated from the culture broth of Lepteutypa sp. KT4162. Neither conventional NMR analyses nor DFT (density functional theory)-based computationally assisted chemical shift discussions were sufficient to elucidate the relative configuration of the 1,4-epoxydiol moiety. A combined analysis using the calculated nJCH values and HMBC spectra was helpful to establish the relative configuration. The absolute configurations of 1-5 were determined using DFT-based ECD (electronic circular dichroism) spectral analysis. Biological assays of these compounds revealed that 2 potently inhibits HIV-1 integrase without cytotoxicity.

[1]  Kazuaki Tanaka,et al.  Isolation, Identification, and DFT-based Conformational Analysis of Sesquikarahanadienone and its Congeners from Freshwater Dothideomycetes Neohelicascus aquaticus KT4120 , 2022, Bulletin of the Chemical Society of Japan.

[2]  K. Konno,et al.  Cyclohumulanoid Sesquiterpenes from the Culture Broth of the Basidiomycetous Fungus Daedaleopsis tricolor † , 2021, Molecules.

[3]  Kazuaki Tanaka,et al.  Isolation and structural elucidation of novel fusicoccan dehydroxypericonicin A from Roussoella sp. , 2021, Bioscience, biotechnology, and biochemistry.

[4]  M. Gordon,et al.  HIV-1 integrase strand transfer inhibitors: A review of current drugs, recent advances and drug resistance. , 2021, International journal of antimicrobial agents.

[5]  Kazuaki Tanaka,et al.  Cyclohelminthol CPs: Scope and Limitations of Density Functional Theory-Based Structural Elucidation of Natural Products. , 2021, The Journal of organic chemistry.

[6]  Kazuaki Tanaka,et al.  DFT Supported Structural Revision of Seiricardines , 2020, Bulletin of the Chemical Society of Japan.

[7]  Kazuaki Tanaka,et al.  Isolation of Peribysins O, P, and Q from Periconia macrospinosa KT3863 and Configurational Reinvestigation of Peribysin E Diacetate from Periconia byssoides OUPS-N133. , 2019, Journal of natural products.

[8]  Kazuaki Tanaka,et al.  Cyclohelminthols Y1-Y4 Metabolites Possessing Two Spirocyclopropanes in Their Structure. , 2018, Journal of Organic Chemistry.

[9]  Kazuaki Tanaka,et al.  Cyclohelminthol X, a Hexa-Substituted Spirocyclopropane from Helminthosporium velutinum yone96: Structural Elucidation, Electronic Circular Dichroism Analysis, and Biological Properties. , 2017, The Journal of organic chemistry.

[10]  H. Koshino,et al.  Neomacrophorin X, a [4.4.3]Propellane-Type Meroterpenoid from Trichoderma sp. 1212-03. , 2017, Journal of natural products.

[11]  Otto-Wilhelm Merten,et al.  Production of lentiviral vectors , 2016, Molecular therapy. Methods & clinical development.

[12]  T. Nehira,et al.  Neomacrophorin I, II, and III, novel drimenyl cyclohexanes with hydroxylated butanoates from Trichoderma sp. 1212-03 , 2014 .

[13]  M. K. Harper,et al.  Thiazoline peptides and a tris-phenethyl urea from Didemnum molle with anti-HIV activity. , 2012, Journal of natural products.

[14]  Jonathan M Goodman,et al.  Assigning stereochemistry to single diastereoisomers by GIAO NMR calculation: the DP4 probability. , 2010, Journal of the American Chemical Society.

[15]  N. Akhtar,et al.  New Bioactive 2,3‐Epoxycyclohexenes and Isocoumarins from the Endophytic Fungus Phomopsis sp. from Laurus Azorica , 2009 .

[16]  N. Fusetani,et al.  Enzyme inhibitors from marine invertebrates. , 2007, Journal of natural products.

[17]  J. Mallet,et al.  Lentiviral vectors with a defective integrase allow efficient and sustained transgene expression in vitro and in vivo , 2006, Proceedings of the National Academy of Sciences.

[18]  F. Jensen.  The Basis Set Convergence of Spin-Spin Coupling Constants Calculated by Density Functional Methods. , 2006, Journal of chemical theory and computation.

[19]  Yong Sup Lee,et al.  Vanillic acid glycoside and quinic acid derivatives from Gardeniae Fructus. , 2006, Journal of natural products.

[20]  G. Mehta,et al.  Enantioselective total synthesis of a novel polyketide natural product (+)-integrasone, an HIV-1 integrase inhibitor. , 2005, Chemical communications.

[21]  R. Hoffman.  Structure Determination of Organic Compounds , 2005 .

[22]  D. Hazuda,et al.  Isolation, structure, absolute stereochemistry, and HIV-1 integrase inhibitory activity of integrasone, a novel fungal polyketide. , 2004, Journal of natural products.

[23]  L. Maes,et al.  Plant substances as anti-HIV agents selected according to their putative mechanism of action. , 2004, Journal of natural products.

[24]  D. Hazuda,et al.  Chemistry and structure-activity relationship of HIV-1 integrase inhibitor integracide B and related natural products. , 2003, Journal of natural products.

[25]  D. Hazuda,et al.  Isolation, structure, and HIV-1 integrase inhibitory activity of Cytosporic acid, a fungal metabolite produced by a Cytospora sp. , 2003, Journal of natural products.

[26]  O. Genilloud,et al.  The complestatins as HIV-1 integrase inhibitors. Efficient isolation, structure elucidation, and inhibitory activities of isocomplestatin, chloropeptin I, new complestatins, A and B, and acid-hydrolysis products of chloropeptin I. , 2001, Journal of natural products.

[27]  D J Newman,et al.  Natural product-based anti-HIV drug discovery and development facilitated by the NCI developmental therapeutics program. , 2001, Journal of natural products.

[28]  A. Hsu,et al.  Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. , 1998, Clinical pharmacokinetics.

[29]  H. Kim,et al.  A new flavonol glycoside gallate ester from Acer okamotoanum and its inhibitory activity against human immunodeficiency virus-1 (HIV-1) integrase. , 1998, Journal of natural products.

[30]  H. Langtry,et al.  Zidovudine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. , 1989, Drugs.