Noam Greenspoon

Organo tin nucleophiles iii. Palladium catalyzed reductive cleavage of allylic heterosubstituents with tin hydride

Abstract Tributyl tin hydride, serving as an efficient hydride transfer agent, allows highly chemoselective palladium catalyzed reductions of allylic heterosubstituents even in presence of aldehydes, benzyl acetate and benzyl chloride.

Zinc chloride-mediated conjugate reduction with silicon hydrides and palladium(O) catalyst

Abstract The chemistry of diphenylsilane/Pd(O), a system previously known to reduce only allylic heterosubstituents, has been radically altered by addition of catalytic amounts of zinc chloride, enabling efficient conjugate reduction of α,β-unsaturated ketones and aldehydes.

Inhibition of CD4+ T lymphocyte binding to fibronectin and immune-cell accumulation in inflammatory sites by non-peptidic mimetics of Arg-Gly-Asp.

The Arg‐Gly‐Asp (RGD) cell adhesion motif has been demonstrated in various studies to play a pivotal rote in leucocyte and platelet interactions with plasma and extracellular matrix (ECM) glycoproteins. The recognition the RGD sequence is mediated by heterodimeric receptors designated integrins of the β1 subfamily, expressed on distinct cell types, including T lymphocytes. We have recently shown that flexible non‐peptidie mimetics of RGD, in which the two ionic side groups were separated by a linear spacer of 11 atoms, bound specifically to the platelet integrin α11bβ3, and inhibited T cell‐mediated immune responses. The present study was designed to (i) further characterize the structural requirements for RGD interactions with CD4+T cells, and (ii) examine the mechanisms by which the RGD mimetics interfere with immune cell reactivity in vivo. We now report that freezing the conformational degrees of freedom in the spacer chain, which fixes the relative orientation of the guanidinium and carboxylate side groups in a favourable manner, resutls in a higher level of inhibition of T cell binding to immobilized fibronectin, an RGD‐containing ECM glycoprotein. In vitro, treatment of mice with relatively low doses of the RGD mimetics, but not the RGD peptide, inhibited the elicitation of an adoptively transferred DTH reaction. This inhibition was achieved by direct impairment the ability of antigen‐primed lymph node cells to migrate and accumulate in inflammatory sites. Hence, we suggest that the design and production of non‐peptidic mimetics of RGD offers a novel approach to study defined parameters related to the structure‐function requirements of small adhesion epitopes. Furthermore, this approach could be used therapeutically to inhibit pathological processes which depend on RCJD recognition.

Partial Reduction of Enones, Styrenes and Related Systems

Although the conjugated systems of polyenes and unsaturated carbonyl compounds are somewhat similar in terms of structure and bonding, their chemical reactivities are significantly different. The number of available methods for partial reduction of unsaturated carbonyls is overwhelmingly greater than the number of known methods for polyene reduction, and this review deals almost exclusively with unsaturated carbonyl compounds, concentrating upon the reduction of the CC double bond. We subdivide it according to synthetic methodology rather than substrate nature, an arrangement that provides a general view clarifying the scope and limitations of a given method and saving repetition. Dienes and styrenes are discussed at the end of the review.

Treatment of immune cell-mediated liver damage by nonpeptidic mimetics of the extracellular matrix-associated Arg-Gly-Asp epitope.

The etiology of T-cell-mediated liver injury involves the migration of immune cells, notably CD4+ T lymphocytes, into liver tissues. This process is mediated primarily by integrin-recognition of the sub-endothelium basement membranes and the extracellular matrix. The Arg-Gly-Asp-containing peptide, a major cell-adhesive ligand of extracellular matrix, is present in various plasma- and matrix-glycoproteins, such as fibronectin. Recently, we have described the design and usage of nonpeptide mimetics of Arg-Gly-Asp which bind specifically to integrins, and thereby, inhibit T cell immunity in vivo. We examined the efficacy of Arg-Gly-Asp-mimetics as potential therapeutic compounds for the treatment of experimental T-cell-mediated liver injury induced in mice by injection of Concanavalin-A. We now report that the Arg-Gly-Asp-mimetics specifically inhibited the binding of murine T cells to fibronectin, but did not affect the proliferative response of these cells in vitro. Intraperitoneal or oral administration of the Arg-Gly-Asp-mimetics but not the Arg-Gly-Asp-containing peptide, inhibited liver damage in mice if given before their inoculation with Con-A, as manifested by a lesser elevation in their serum levels of hepatic enzymes. The inhibitory effect of the Arg-Gly-Asp-mimetics was dose-dependent, the ED50 of the tested molecules being in the range of 100 micrograms per mouse and reaching maximal effect, e.g. approximately 95% inhibition, at 500 micrograms per mice. Thus, the Arg-Gly-Asp-mimetics described here may be used therapeutically to prevent immune-cell-mediated acute or chronic pathological reactions in the liver.