Matthew Shair was born and raised in Boston, Massachusetts. Although he explored other parts of the country during undergraduate (University of Rochester) and graduate school (Yale and Columbia Universities), he eventually returned home for a post-doctoral position and a faculty appointment at Harvard.

Bioorganic/Chemical Biology/Organic

Lee AS, Shair MD. Synthesis of the C4-Epi-Lomaiviticin B Core Reveals Subtle Stereoelectronic Effects. Org Lett. 2013.Abstract An efficient synthesis of the C4-epi-lomaiviticin B core is reported. The synthesis features a diastereoselective anionic formal furan Diels-Alder reaction and a stereoselective oxidative enolate dimerization. During the investigation, subtle yet critical stereoelectronic effects imparted by the C4-stereocenter were observed.Sparling BA, Moebius DC, Shair MD. Enantioselective total synthesis of hyperforin. J Am Chem Soc. 2013;135(2):644-7.Abstract A modular, 18-step total synthesis of hyperforin is described. The natural product was quickly accessed using latent symmetry elements, whereby a group-selective, Lewis acid-catalyzed epoxide-opening cascade cyclization was used to furnish the bicyclo[3.3.1]nonane core and set two key quaternary stereocenters.Lu L, Hannoush RN, Goess BC, Varadarajan S, Shair MD, Kirchhausen T. The small molecule dispergo tubulates the endoplasmic reticulum and inhibits export. Mol Biol Cell. 2013;24(7):1020-9.Abstract The mammalian endoplasmic reticulum (ER) is an organelle that maintains a complex, compartmentalized organization of interconnected cisternae and tubules while supporting a continuous flow of newly synthesized proteins and lipids to the Golgi apparatus. Using a phenotypic screen, we identify a small molecule, dispergo, that induces reversible loss of the ER cisternae and extensive ER tubulation, including formation of ER patches comprising densely packed tubules. Dispergo also prevents export from the ER to the Golgi apparatus, and this traffic block results in breakdown of the Golgi apparatus, primarily due to maintenance of the constitutive retrograde transport of its components to the ER. The effects of dispergo are reversible, since its removal allows recovery of the ER cisternae at the expense of the densely packed tubular ER patches. This recovery occurs together with reactivation of ER-to-Golgi traffic and regeneration of a functional Golgi with correct morphology. Because dispergo is the first small molecule that reversibly tubulates the ER and inhibits its export function, it will be useful in studying these complex processes. Liau BB, Milgram BC, Shair MD. Total syntheses of HMP-Y1, hibarimicinone, and HMP-P1. J Am Chem Soc. 2012;134(40):16765-72.Abstract Total syntheses of HMP-Y1, atrop-HMP-Y1, hibarimicinone, atrop-hibarimicinone, and HMP-P1 are described using a two-directional synthesis strategy. A novel benzyl fluoride Michael-Claisen reaction sequence was developed to construct the complete carbon skeleton of HMP-Y1 and atrop-HMP-Y1 via a symmetrical, two-directional, double annulation. Through efforts to convert HMP-Y1 derivatives to hibarimicinone and HMP-P1, a biomimetic mono-oxidation to desymmetrize protected HMP-Y1 was realized. A two-directional unsymmetrical double annulation and biomimetic etherification was developed to construct the polycyclic and highly oxidized skeleton of hibarimicinone, atrop-hibarimicinone, and HMP-P1. The use of a racemic biaryl precursor allowed for the synthesis of both hibarimicinone atropisomers and provides the first confirmation of the structure of atrop-hibarimicinone. Additionally, this work documents the first reported full characterization of atrop-hibarimicinone, HMP-Y1, atrop-HMP-Y1, and HMP-P1. Last, a pH-dependent rotational barrier about the C2-C2' bond of hibarimicinone was discovered, which provides valuable information necessary to achieve syntheses of the glycosylated congeners of hibarimicinone. Burgett AWG, Poulsen TB, Wangkanont K, Anderson RD, Kikuchi C, Shimada K, Okubo S, Fortner KC, Mimaki Y, Kuroda M, et al. Natural products reveal cancer cell dependence on oxysterol-binding proteins. Nat Chem Biol. 2011;7(9):639-47.Abstract Cephalostatin 1, OSW-1, ritterazine B and schweinfurthin A are natural products that potently, and in some cases selectively, inhibit the growth of cultured human cancer cell lines. The cellular targets of these small molecules have yet to be identified. We have discovered that these molecules target oxysterol binding protein (OSBP) and its closest paralog, OSBP-related protein 4L (ORP4L)--proteins not known to be involved in cancer cell survival. OSBP and the ORPs constitute an evolutionarily conserved protein superfamily, members of which have been implicated in signal transduction, lipid transport and lipid metabolism. The functions of OSBP and the ORPs, however, remain largely enigmatic. Based on our findings, we have named the aforementioned natural products ORPphilins. Here we used ORPphilins to reveal new cellular activities of OSBP. The ORPphilins are powerful probes of OSBP and ORP4L that will be useful in uncovering their cellular functions and their roles in human diseases.Milgram BC, Liau BB, Shair MD. Gram-scale synthesis of the A'B'-subunit of angelmicin B. Org Lett. 2011;13(24):6436-9.Abstract A gram-scale enantiospecific synthesis of the A'B'-subunit of angelmicin B is reported. The synthesis involves a Lewis acid catalyzed contrasteric Diels-Alder reaction and a tandem silyl zincate 1,6-addition/enolate oxidation sequence. Lee HG, Ahn JY, Lee AS, Shair MD. Enantioselective synthesis of the lomaiviticin aglycon full carbon skeleton reveals remarkable remote substituent effects during the dimerization event. Chemistry. 2010;16(44):13058-62.Liau BB, Shair MD. Total synthesis of (+)-fastigiatine. J Am Chem Soc. 2010;132(28):9594-5.Abstract The first total synthesis of the Lycopodium alkaloid (+)-fastigiatine has been accomplished in 15 steps and 30% overall yield from known compounds. Noteworthy transformations include a convergent fragment coupling via a nucleophilic cyclopropane opening, a highly diastereoselective formal [3 + 3]-cycloaddition, and a transannular Mannich reaction to construct the core of the natural product.Fortner KC, Kato D, Tanaka Y, Shair MD. Enantioselective synthesis of (+)-cephalostatin 1. J Am Chem Soc. 2010;132(1):275-80.Abstract An efficient synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-D-pyrrolosamine glycal of lomaiviticin A (1) and lomaiviticin B (2) is described. The synthesis is highlighted by the epimerization of the L-threonine-derived oxazolidine 10 to oxazolidine 11. This key epimerization reaction, which serves to establish the correct relative configuration of the carbohydrate unit, was made possible only after conformational analysis indicated that substituted oxazolidines may adopt conformations that preclude enolization. Morris WJ, Shair MD. Stereoselective synthesis of 2-deoxy-beta-glycosides using anomeric O-alkylation/arylation. Org Lett. 2009;11(1):9-12.Abstract Anomeric O-alkylation/arylation is applied to the synthesis of 2-deoxy-beta-glycosides. Treatment of lactols with NaH in dioxane followed by the addition of electrophiles leads to the formation of 2-deoxy-beta-glycosides in high yield and high selectivity. The high beta-selectivity observed here demonstrates a powerful stereoelectronic effect for the stereoselective formation of acetals under kinetic control. Lee HM, Nieto-Oberhuber C, Shair MD. Enantioselective synthesis of (+)-cortistatin a, a potent and selective inhibitor of endothelial cell proliferation. J Am Chem Soc. 2008;130(50):16864-6.Abstract Phillips ST, Shair MD. Syntheses of the eastern halves of ritterazines B, F, G, and H, leading to reassignment of the 5,5-spiroketal stereochemistry of ritterazines B and F. J Am Chem Soc. 2007;129(20):6589-98.Abstract The ritterazine class of natural products comprises 26 compounds-all of which are spiroketal-containing steroidal heterodimers-that inhibit the proliferation of cultured human cancer cell lines with IC50 values in the low nanomolar range. Little is known about their chemistry, cellular target(s), or mechanism(s) of growth inhibition, due primarily to the small amount of material available from natural sources. In this paper we report syntheses of the eastern halves of ritterazines B, F, G, and H and address the energetic and mechanistic aspects of spiroketal equilibration for each. These studies have led to reassignment of the 5,5-spiroketal stereochemistry of ritterazines B and F, and they have enabled us to propose a quantitative description of the natural distribution of these ritterazine compounds.Fortner KC, Shair MD. Stereoelectronic effects dictate mechanistic dichotomy between Cu(II)-catalyzed and enzyme-catalyzed reactions of malonic acid half thioesters. J Am Chem Soc. 2007;129(5):1032-3. Pelish HE, Ciesla W, Tanaka N, Reddy K, Shair MD, Kirchhausen T, Lencer WI. The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cells. Biochem Pharmacol. 2006;71(12):1720-6.Abstract Cyclic AMP- (cAMP) and calcium-dependent agonists stimulate chloride secretion through the coordinated activation of distinct apical and basolateral membrane channels and ion transporters in mucosal epithelial cells. Defects in the regulation of Cl- transport across mucosal surfaces occur with cystic fibrosis and V. cholerae infection and can be life threatening. Here we report that secramine B, a small molecule that inhibits activation of the Rho GTPase Cdc42, reduced cAMP-stimulated chloride secretion in the human intestinal cell line T84. Secramine B interfered with a cAMP-gated and Ba2+-sensitive K+ channel, presumably KCNQ1/KCNE3. This channel is required to maintain the membrane potential that sustains chloride secretion. In contrast, secramine B did not affect the Ca2+-mediated chloride secretion pathway, which requires a separate K+ channel activity from that of cAMP. Pirl1, another small molecule structurally unrelated to secramine B that also inhibits Cdc42 activation in vitro, similarly inhibited cAMP-dependent but not Ca2+-dependent chloride secretion. These results suggest that Rho GTPases may be involved in the regulation of the chloride secretory response and identify secramine B an inhibitor of cAMP-dependent K+ conductance in intestinal epithelial cells.Pelish HE, Peterson JR, Salvarezza SB, Rodriguez-Boulan E, Chen J-L, Stamnes M, Macia E, Feng Y, Shair MD, Kirchhausen T. Secramine inhibits Cdc42-dependent functions in cells and Cdc42 activation in vitro. Nat Chem Biol. 2006;2(1):39-46.Abstract Inspired by the usefulness of small molecules to study membrane traffic, we used high-throughput synthesis and phenotypic screening to discover secramine, a molecule that inhibits membrane traffic out of the Golgi apparatus by an unknown mechanism. We report here that secramine inhibits activation of the Rho GTPase Cdc42, a protein involved in membrane traffic, by a mechanism dependent upon the guanine dissociation inhibitor RhoGDI. RhoGDI binds Cdc42 and antagonizes its membrane association, nucleotide exchange and effector binding. In vitro, secramine inhibits Cdc42 binding to membranes, GTP and effectors in a RhoGDI-dependent manner. In cells, secramine mimics the effects of dominant-negative Cdc42 expression on protein export from the Golgi and on Golgi polarization in migrating cells. RhoGDI-dependent Cdc42 inhibition by secramine illustrates a new way to inhibit Rho GTPases with small molecules and provides a new means to study Cdc42, RhoGDI and the cellular processes they mediate.Goess BC, Hannoush RN, Chan LK, Kirchhausen T, Shair MD. Synthesis of a 10,000-membered library of molecules resembling carpanone and discovery of vesicular traffic inhibitors. J Am Chem Soc. 2006;128(16):5391-403.Abstract Split-and-pool synthesis of a 10,000-membered library of molecules resembling the natural product carpanone has been achieved. The synthesis features development of solid-phase multicomponent reactions between nitrogen nucleophiles, enones, and hydroxylamines, and a solid-phase application of the Huisgen cycloaddition affording substituted triazoles. The synthesis was performed in high-capacity (500 microm) polystyrene beads using a one bead-one stock solution strategy that enabled phenotypic screens of the resulting library. Using whole-cell fluorescence imaging, we discovered a series of molecules from the carpanone-based library that inhibit exocytosis from the Golgi apparatus. The most potent member of this series has an IC(50) of 14 microM. We also report structure-activity relationships for the molecules exhibiting this interesting phenotype. These inhibitors of exocytosis may be useful reagents for the study of vesicular traffic. Magdziak D, Lalic G, Lee HM, Fortner KC, Aloise AD, Shair MD. Catalytic enantioselective thioester aldol reactions that are compatible with protic functional groups. J Am Chem Soc. 2005;127(20):7284-5.Abstract