Diverted total synthesis: preparation of a focused library of latrunculin analogues and evaluation of their actin-binding properties.
(73/688)
Two largely catalysis-based and highly convergent total syntheses of latrunculin A (1) and B (2) were diverted to the preparation of a focused library of analogues of these potent actin-binding macrolides that enjoy widespread use in chemical biology. Because the chosen route allows for structural variations of all characteristic parts of the natural leads, it was possible to map the previously largely unknown structure/activity profile of this class of bioactive natural products. This led to the discovery that the removal of the methyl branches decorating the macrocycle in 2 engenders a significant increase in potency, while streamlining the synthesis to a considerable extent. Moreover, compelling evidence is provided that the conspicuous 2-thiazolidinone ring present in all naturally occurring latrunculins may be an optimal but not an essential structural motif for actin binding because it can be replaced by an oxazolidinone moiety with only slight loss in efficacy. Likewise, the inversion of the absolute configuration of the chiral center at C.16 is well accommodated. From the purely chemical perspective, this investigation attests to the maturity of alkyne metathesis, a method that has received attention as efficient means for the formation of macrocycles only recently. (+info)
African herbal medicines in the treatment of HIV: Hypoxis and Sutherlandia. An overview of evidence and pharmacology.
(74/688)
In Africa, herbal medicines are often used as primary treatment for HIV/AIDS and for HIV-related problems. In general, traditional medicines are not well researched, and are poorly regulated. We review the evidence and safety concerns related to the use of two specific African herbals, which are currently recommended by the Ministry of Health in South Africa and member states for use in HIV: African Potato and Sutherlandia. We review the pharmacology, toxicology and pharmacokinetics of these herbal medicines. Despite the popularity of their use and the support of Ministries of Health and NGOs in some African countries, no clinical trials of efficacy exist, and low-level evidence of harm identifies the potential for drug interactions with antiretroviral drugs. Efforts should be made by mainstream health professionals to provide validated information to traditional healers and patients on the judicious use of herbal remedies. This may reduce harm through failed expectations, pharmacologic adverse events including possible drug/herb interactions and unnecessary added therapeutic costs. Efforts should also be directed at evaluating the possible benefits of natural products in HIV/AIDS treatment. (+info)
Adventitious reactions of alkene monooxygenase reveal common reaction pathways and component interactions among bacterial hydrocarbon oxygenases.
(75/688)
Alkene monooxygenase (AMO) from Rhodococcus rhodochrous (formerly Nocardia corallina) B-276 belongs to a family of multicomponent nonheme binuclear iron-centre oxygenases that includes the soluble methane monooxygenases (sMMOs) found in some methane-oxidizing bacteria. The enzymes catalyse the insertion of oxygen into organic substrates (mostly hydrocarbons) at the expense of O2 and NAD(P)H. AMO is remarkable in its ability to oxidize low molecular-mass alkenes to their corresponding epoxides with high enantiomeric excess. sMMO and other well-characterized homologues of AMO exhibit two adventitious activities: (1) turnover-dependent inhibition by alkynes and (2) activation by hydrogen peroxide in lieu of oxygen and NAD(P)H (the peroxide shunt reaction). Previous studies of the AMO had failed to detect these activities and opened the possibility that the mechanism of AMO might be fundamentally different from that of its homologues. Thanks to improvements in the protocols for cultivation of R. rhodochrous B-276 and purification and assay of AMO, it has been possible to detect and characterize turnover-dependent inhibition of AMO by propyne and ethyne and activation of the enzyme by hydrogen peroxide. These results indicate a similar mechanism to that found in sMMO and also, unexpectedly, that the enantiomeric excess of the chiral epoxypropane product is significantly reduced during the peroxide shunt reaction. Inhibition of the oxygen/NADH-activated reaction, but not the peroxide shunt, by covalent modification of positively charged groups revealed an additional similarity to sMMO and may indicate very similar patterns of intersubunit interactions and/or electron transfer in both enzyme complexes. (+info)
Practical and highly enantioselective synthesis of beta-alkynyl-beta-amino esters through Ag-catalyzed asymmetric mannich reactions of silylketene acetals and alkynyl imines.
(76/688)
[reaction: see text] A readily available iso-leucine-based phosphine ligand is used to promote Ag-catalyzed Mannich reactions between silylketene acetals and various alkynyl imines. Reactions can be effected in the presence of 5 mol % catalyst, without the need for rigorous exclusion of air, and with commercially available solvents (without purification) to afford the desired beta-alkynyl-beta-amino esters in 84-94% ee and 61-91% isolated yield. (+info)
anti-1,2-Diols via Ni-catalyzed reductive coupling of alkynes and alpha-oxyaldehydes.
(77/688)
[reaction: see text] Ni-catalyzed reductive coupling of aryl alkynes (1) and enantiomerically enriched alpha-oxyaldehydes (2) afford differentiated anti-1,2-diols (3) with high diastereoselectivity and regioselectivity, despite the fact that the methoxymethyl (MOM) and para-methoxybenzyl (PMB) protective groups typically favor syn-1,2-diol formation in carbonyl addition reactions of this family of aldehydes. (+info)
An alkyne hydrosilylation-oxidation strategy for the selective installation of oxygen functionality.
(78/688)
Alkynes bearing propargylic, homopropargylic, and bishomopropargylic hydroxyl groups are shown to serve as precursors for ketone or alpha-hydroxy ketone functionality. The approach hinges on the intermediacy of vinylsilanes created through regioselective hydrosilylation catalyzed by the complex [Cp*Ru(MeCN)3]PF6. Several oxidative pathways of linear and cyclic vinylsilanes are studied, and the possibility of diastereoselective epoxidation of cyclic vinylsilanes is demonstrated. The sequences constitute the equivalent of stereoselective aldol, homo-aldol, and bishomo-aldol type processes. The method is applied to a short synthesis of the piperidine alkaloid, spectaline. (+info)
Catalytic asymmetric alkynylation of alpha-imino ester: a versatile approach to optically active unnatural alpha-amino acid derivatives.
(79/688)
The catalytic asymmetric introduction of alkynyl functionality to alpha-amino acid derivatives was realized by the direct addition of terminal alkynes to alpha-imino ester in the presence of chiral Cu(I) complex under mild reaction conditions. Owing to the rich chemistry to which alkyne can be subjected, the present system provides a remarkably versatile tool for the construction of optically active alpha-amino acid derivatives. Good yields and enantiomeric excess values were achieved with an array of terminal alkynes and challenging, biologically active, unnatural alpha-amino acid derivatives could be conveniently obtained. (+info)
Intermolecular rhodium-catalyzed [2+2+2] carbocyclization reactions of 1,6-enynes with symmetrical and unsymmetrical alkynes.
(80/688)
The crossed intermolecular rhodium-catalyzed [2+2+2] carbocyclization of carbon and heteroatom tethered 1,6-enynes can be accomplished with symmetrical and unsymmetrical alkynes, to afford the corresponding bicyclohexadienes in an efficient and highly selective manner. (+info)