L-696,474, a novel cytochalasin as an inhibitor of HIV-1 protease. III. Biological activity.

Lingham, Russell B.; Hsu, Amy; Silverman, Keith C.; Bills, Gerald F.; Dombrowski, Anne W.; Goldman, Mark E.; Darke, Paul L.; HUANG, LEE; Koch, Gregory; Ondeyka, John G.; Goetz, Michael

doi:10.7164/antibiotics.45.686

Cited by 52 publications

(33 citation statements)

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“…Such information combined with advances in analytical (91) and molecular (92) (83). This structure confirms the prediction that had been based on the alignment of 11 sequences from a range of species that the conserved leucines (highlighted in yellow) would be oriented toward each other along the faces of neighboring helices. As predicted, the helices cross the DNA in the major goove.…”

Section: Selecting Sources To Be Screened For Drugs and Leadssupporting

confidence: 82%

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Chemical ecology: a view from the pharmaceutical industry.

Caporale

1995

Proc. Natl. Acad. Sci. U.S.A.

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Biological diversity reflects an underlying molecular diversity. The molecules found in nature may be regarded as solutions to challenges that have been confronted and overcome during molecular evolution. As our understanding ofthese solutions deepens, the efficiency with which we can discover and/or design new treatments for human disease grows. Nature assists our drug discovery efforts in a variety ofways. Some compounds synthesized by microorganisms and

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Section: Selecting Sources To Be Screened For Drugs and Leadssupporting

confidence: 82%

“…While new structures that inhibit the HIV protease have emerged from natural product screens (11,12) [one structure that inhibits aspartyl proteases, the statine moiety, had been discovered through screening bacterial natural products before the emergence of HIV (10) (9,13,14).…”

Section: Selection Of Drug Discovery Targetsmentioning

confidence: 99%

Chemical ecology: a view from the pharmaceutical industry.

Caporale

1995

Proc. Natl. Acad. Sci. U.S.A.

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“…The HRFABMS provided the same molecular weight of 527.27. The corresponding molecular formula of both was established to be C 29 H 37 NO 8 , which indicates that 6 and 8 possessed two and three extra oxygen atoms compared to their precursors 7 and 1, respectively. The IR spectra of 6 and 8 confirmed the conservation of the main functionalities initially present in 1, i.e.…”

Section: Structures Of Triepoxycytochalasins 6 Andmentioning

confidence: 99%

“…[4 -6] The cytochalasins have also been reported to exhibit antibiotic and anti-tumour activities, [7] and to inhibit HIV-1 protease. [8] The synthesis and biological evaluation of cytochalasin of various types are well documented. [9 -12] The most unusual property of the cytochalasins is their ability to cause cells to extrude their nuclei, leading to the formation of nuclei-free cells.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, complete ¹H and ¹³C NMR assignment and crystal structure of novel epoxide derivatives of cytochalasin B

Steyn¹,

Breytenbach²,

Botha³

et al. 2008

Magnetic Reson in Chemistry

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Five novel epoxide derivatives of cytochalasin B were synthesized. Reaction of cytochalasin B with t-BHP and BuLi led to selective epoxidation of the C-21/22 double bond to give a single monoepoxide, while reaction with m-CPBA yielded two diepoxides. Reaction of the monoepoxide with m-CPBA yielded two triepoxides. The relative configurations of the epoxides were elucidated by analogy with the natural product by means of spectroscopic methods; full assignment of NMR signals was achieved, and the absolute configuration was confirmed by X-ray crystallography.

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“…Cytochalasins have also been reported to exhibit diverse biological activities that are unrelated to actin binding. As examples, L-696,474 (2) inhibits HIV-1 protease (17)(18)(19)(20), cytochalasin B (1) inhibits glucose transport (21), cytochalasin H derivatives regulate plant growth (22), and cytochalasin E inhibits angiogenesis (23). Few naturally derived structural platforms can rival the cytochalasins in terms of their breadth of activities in different biological processes.…”

mentioning

confidence: 99%

An enantioselective, modular, and general route to the cytochalasins: Synthesis of L-696,474 and cytochalasin B

Haidle

Myers

2004

Proc. Natl. Acad. Sci. U.S.A.

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The cytochalasins are structurally complex natural products with a broad range of apparently unrelated effects in different biological systems. Different members of the family have variously demonstrated inhibitory activity toward the formation of actin filaments, toward the functioning of HIV protease, and toward the process of angiogenesis. The structural series is defined by a largely conserved, rigid bicyclic isoindolone core that is fused to a macrocyclic appendage. The latter structural component varies widely within the cytochalasins and seems to play an important role in the determination of biological activity. In this work, we describe the development of a convergent and enantioselective synthetic route to the cytochalasins that allows for the late-stage introduction of macrocyclic appendages of different sizes and constitutions. We illustrate the route with the synthesis of the 14-membered macrolactone cytochalasin B (1, an inhibitor of the formation of actin filaments) and the 11-membered macrocarbocyclic cytochalasin L-696,474 (2, an inhibitor of HIV protease) by using common precursors.

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L-696,474, a novel cytochalasin as an inhibitor of HIV-1 protease. III. Biological activity.

Cited by 52 publications

References 0 publications

Chemical ecology: a view from the pharmaceutical industry.

Chemical ecology: a view from the pharmaceutical industry.

Synthesis, complete ¹H and ¹³C NMR assignment and crystal structure of novel epoxide derivatives of cytochalasin B

An enantioselective, modular, and general route to the cytochalasins: Synthesis of L-696,474 and cytochalasin B

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L-696,474, a novel cytochalasin as an inhibitor of HIV-1 protease. III. Biological activity.

Cited by 52 publications

References 0 publications

Chemical ecology: a view from the pharmaceutical industry.

Chemical ecology: a view from the pharmaceutical industry.

Synthesis, complete 1H and 13C NMR assignment and crystal structure of novel epoxide derivatives of cytochalasin B

An enantioselective, modular, and general route to the cytochalasins: Synthesis of L-696,474 and cytochalasin B

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Synthesis, complete ¹H and ¹³C NMR assignment and crystal structure of novel epoxide derivatives of cytochalasin B