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Phospho-glycoprotein (P-gp) is an efflux transporter expressed in many organs (ex: kidney, lung, liver and spleen) and in hormone producing or responsive tissues (ex: adrenal cortex, testis and placenta). It is involved in many important physiological functions. Among them the major one is extrusion of xenobiotics in order to detoxify the cells. This property of P-gp is associated with multidrug resistance (MDR) for many pathological conditions. While the experimental determination of three-dimensional structure is not yet successful, the transmembrane (TM) 5, 6, 11 and 12 are sensitive to mutations and contain substrate binding sites. Designing of potential and selective inhibitors of P-gp is still hampered by a lack of information upon the three dimensional structure of P-gp. The design of P-gp inhibitors was traditionally driven by quantitative structure activity relationship studies, which is complicated by factors such as different types of assays, multiple drug binding sites and diverse chemical structures. Clearly a conclusive and predictive SAR does not seem to be practical, despite progress in the last few years towards more specific SAR suggesting well defined structural features responsible for activity. Advances made recently in solving the crystal structure of prokaryotic ATP binding cassette proteins (ABC) transporters, Ec-MsbA, Vc-MsbA and BtuCD yielded suitable templates for construction of homology models of P-gp. Few molecular dynamics (MD) simulations aimed at elucidating the functional dynamics of ABC transporters have provided useful insights to their mechanism and structure. The present review aims at the general overview of importance, expression, structure, organization and drug binding sites of P-gp. This review also highlights recent developments in the homology modeling, molecular dynamics simulations of P-gp and progress in QSAR, pharmacophore modeling of P-gp modulators.

The asymmetric total synthesis of both enantiomers of (+)-and (-)-vittatalactone has been achieved using a desymmetrization strategy to create three methyl chiral centers. The key steps in these total syntheses are Myers asymmetric alkylation, coppercatalyzed alkylation, 2,2,6,6-tetramethyl-1-piperidinyloxyl-(diacetoxyiodo)benzene [TEMPO-PhI(OAc 2 )] promoted oxidation and p-toluenesulfonyl chloride mediated lactonization. The products are obtained in good overall yields employing linear synthetic sequences.Polydeoxypropionates are an important class of biologically active molecules and the development of methods for their synthesis has led to the discovery of new strategies. The use and application of pheromones is expected to grow more rapidly and widely in the coming years because of increasing concerns of consumers about residual chemicals from agricultural products. The chemical syntheses of such compounds will ensure ample supplies and facilitate their practical use in agriculture and forestry. Vittatalactone, a structurally unique pheromone, was isolated from the striped cucumber beetle, Acalymma vittatum by Francke 1 and coworkers in 2005. It contains a novel trans-configured b-lactone moiety and an all synconfigured tetramethyl substituted alkyl chain as structural features. Breit et al. 2 have assigned the relative and absolute configurations of natural (+)-1a and unnatural (-)-1b 3 vittatalactones through total synthesis. Figure 1 Structures of (+)-and (-)-vittatalactoneIn continuation of our research on synthetic pheromones, 4,5 and our ongoing studies on the synthesis of biologically active molecules by exploiting desymmetrization strategies, the interesting structural features and biological activity of vittatalactone have attracted our attention toward its synthesis. Two total syntheses of vittatalactone have been reported: as key steps, the method of Breit and coworkers involved an o-diphenylphosphinobenzoic acid (o-DPPB) directed allylic substitution, 2 whilst that of Schneider et al. utilized an iridium-catalyzed hydrogenation. 6 Our group previously accomplished the total synthesis of (+)-vittatalactone by using an enzymatic desymmetrization approach. 7 We herein report the total synthesis of both enantiomers of vittatalactone, (+)-1a and (-)-1b, by exploiting our previously developed desymmetrization strategy.Our retrosynthetic strategy is shown in Scheme 1 in which both enantiomers could be easily obtained from the common intermediate 5 by utilizing the appropriate chiral boron reagent.The synthesis of (+)-vittatalactone started from the known triol 3a 8 which was readily obtained from 5 using a desymmetrization approach. Protection of the 1,3-diol moiety was accomplished using 2,2-dimethoxypropane [Me 2 C(OMe) 2 ] 9 and a catalytic amount of p-toluenesulfonic acid in dichloromethane at 0 °C to afford 6a in 85% yield. The primary hydroxy group in 6a was converted into the corresponding iodide to give 7a 10 in 94% yield using triphenylphosphine, imidazole and iodine in toluene at room tempera...

The first stereoselective total synthesis of the proposed structure of the γ‐lactone from Diaporthe sp. SXZ‐19 was achieved by utilizing a convergent pathway. The four stereogenic centers were formed by employing Brown's asymmetric alkoxyallylboration reaction, and a cross‐metathesis reaction was used to construct the trans double bond of the γ‐lactone side chain. This synthesis led to a revision of proposed structural assignment of the natural product.