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Biomedical subjects

S Hanessian

Publications and source records attributed to S Hanessian.

At least 19 recordsLinked to original sources
PubMed2001

Total synthesis of bafilomycin A(1) relying on iterative 1,2-induction in acyclic precursors.

The macrolide bafilomycin A(1) was synthesized starting from D-valine and D-mannitol as chiral progenitors of propionate units. Acyclic subunits corresponding to different parts of the molecule were constructed based on an iterative 1,2-asymmetric induction protocol as a distinctive feature of the synthesis. The assembly of two segments encompassing the entire carbon framework of the macrolide was achieved by using a Stille coupling. The resulting seco-ester was further manipulated to provide crystalline bafilomycin A(1) via a conventional carbodiimide-mediated Keck-type macrolactonization.

Anti-Bacterial Agents↗
PubMed2001

Design and synthesis of matrix metalloproteinase inhibitors guided by molecular modeling. Picking the S(1) pocket using conformationally constrained inhibitors.

Conformationally constrained MMP inhibitors based on a D-proline scaffold were designed using AutoDock as a modeling program. Thus a family of D-proline hydroxamic acids, having differentiated functionality at the site of binding to the S(1) pocket, was synthesized. Biological evaluation showed low nanomolar activity and modest selectivity toward different MMP subclasses, delineating the importance of binding to the S(1) pocket for both activity and selectivity.

Collagenases↗
PubMed2001

A comparative docking study and the design of potentially selective MMP inhibitors.

As part of a program aimed at the design and synthesis of constrained MMP inhibitors, a survey of the reported X-ray and NMR structures of MMP/inhibitor complexes was performed, revealing mutations of key amino acids at different subsites between MMPs. A comparative study of fully automated docking programs AutoDock and DOCK in closely approximating the X-ray crystal structures of ten selected MMP inhibitors was performed. AutoDock proved to be highly reliable, efficient and predictive for a set of inhibitors with less than six atom types.

Binding Sites↗
PubMed2000

Asymmetric conjugate additions of chiral phosphonamide anions to alpha,beta-unsaturated carbonyl compounds. A versatile method for vicinally substituted chirons

Reactions of anions derived from chiral nonracemic allyl, crotyl, and cinnamyl bicyclic C(2)-symmetrical phosphonamides with alpha, beta-unsaturated cyclic ketones, esters, lactones, and lactams take place at the gamma-position of the reagents. The products are diastereomerically pure or enriched beta-substituted carbonyl compounds. The method also provides easy access to vicinal substitution of as many as three stereogenic centers including in some cases quaternary carbon atoms, in a one-pot sequence.

Journal Article↗
PubMed2000

Exploring the chiral space within the active site of alpha-thrombin with a constrained mimic of D-Phe-Pro-Arg--design, synthesis, inhibitory activity, and X-ray structure of an enzyme-inhibitor complex.

An indolizidinone motif with strategically placed substitutents was designed and synthesized as a constrained mimic of D-Phe-Pro-Arg. Low nanomolar inhibition of alpha-thrombin validates the design elements in this inhibitor which also exhibits a 20-fold selectivity for thrombin versus trypsin. An X-ray crystal structure of the inhibitor with alpha-thrombin shows the expected interactions with key amino acids within the active site and some notable changes in positions.

Binding Sites↗
PubMed2000

Asymmetric synthesis of functionalized carbocycles and heterocycles.

Anions of 1-halo-4-hexenyl phosphonamides derived from chiral, enantiopure C2 symmetrical 1,2-diamino cyclohexane react at the gamma-position in conjugate addition reactions with alpha, beta-unsaturated carbonyl compounds such as cyclopentenone, 4-(H)-furanone, pyrroline-2-one, and cinnamates to give functionalized adducts. Addition to imines is also possible. The adducts can be transformed into enantiopure or enriched carbocyclic and heterocyclic compounds bearing useable functionality.

Chemistry↗