Cell adhesion inhibitors synthesis

The same authors have shown that the direct a-amination reaction could also be used to construct the quaternary stereocenter in the enantioselective total synthesis of the cell-adhesion inhibitor BIRT-377 [7b]. The i-proline-derived tetrazole 3c catalyzed the direct a-amination of 3-(4-bromophenyl)-2-methylpropanal 8 with dibenzyl azodicarboxylate 2b to give the amino aldehyde 9 in 95% yield and with... 

Scheme 2.29 The application of organocatalytic enantioselective a-amination reaction of 3-(4-bromophenyl)-2-methylpropanal 8 for the total synthesis of the optically active cell-adhesion inhibitor BIRT-377 [7b].

Synthesis of macrosphelides, natural potent cell-cell adhesion inhibitors having novel three ester linkages in their 16-membered macrocyclic skeleton 05H(65)1741, 05Y140. 

Chowdari and Barbas [22] reported the enantioselective total synthesis of potent cell adhesion inhibitor BIRT-377 (56) in 2005, which has potential for the treatment of a number of inflammatory and immune disorders. Asymmetric synthesis of quaternary amino acids is a challenging task for synthetic chemists [23]. Barbas described the efficient L-proUne-derived, tetrazole-catalyzed direct asymmetric a-amination to construct an aldehyde 55 with the amino-substituted quaternary stereocenter and elaborate this aldehyde into BIRT-377 (56) (Scheme 17.7). 

Synthesis of Cell Adhesion Inhibitors via Crystallization-Driven Dynamic Transformations... 

Hydroxyurea is a ribonucleotide reductase inhibitor that prevents DNA synthesis and traditionally has been used in chemotherapy regimens. Studies in the 1990s also found that hydroxyurea increases HbF levels as well as increasing the number of HbF-containing reticulocytes and intracellular HbF. Other beneficial effects of hydroxyurea include antioxidant properties, reduction of neutrophils and monocytes, increased intracellular water content leading to increased red cell deformability, decreased red cell adhesion to endothelium, and increased levels of nitric oxide, which is a regulator involved in physiologic disturbances.22... 

The quaternization method is also highlighted by the short asymmetric synthesis of cell adhesion molecule BIRT-377 (Scheme 5.24), which is a potent inhibitor of the interaction between intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) [16]. Thus, asymmetricp-bromobenzylation of the alanine derivative 42 (R1 = Me) with (S)-18 under similar phase-transfer conditions as described above gave rise to p-bromobenzylalanine ester 10 in 97% ee (83% yield). A similar asymmetric p-bromobenzylation of alanine ethyl ester 42 (R1 = Me, R= Et) gave the amino ester 47 (R= Et) in 90% ee (86% yield). The amino ester 47 (R = t-Bu or Et) was treated with 3,5-dichlorophenyl isocyanate in the presence of sodium carbonate in dimethylsulfoxide (DMSO) to furnish the hydantoin 48 in 86%... 

Kogan TP, Dupre B, Bui H et al. Novel synthetic inhibitors of selectin-mediated cell adhesion synthesis of l,6-bis(3-(3-carboxymethylphenyl)-4-(2-alpha-D- mannopyranosyloxy)phenyl) hexane (TBC1269). J. Med. Chem. 1998 41 1099-1111. 

Ichikawa Y, Wong C-H (1994) Topochemistry and inhibition of selectin-mediated cell adhesion Chemical-enzymatic synthesis of inhibitors related to E-selectin recognition. In Bock K, Clausen H (eds) Complex carbohydrates in drug research. Structural and functional aspects. Munksgaard, Copenhagen, p 118... 

It was observed that rats with a transient MCA occlusion have a larger brain infarction when recombinant human IL-1 P is injected into the lateral ventricle immediately after reperfusion [7,41]. Similar results have been obtained in rats with a permanent MCA occlusion [7,42]. The intraventricular injection of recombinant human IL-1 p also enhances the formation of brain edema and increases both the number of neutrophils in ischemic areas and neutrophil-endothelial cell adhesion. The most widely recognized functions of IL-1 appear to be the induction of endothelial cell adhesion molecule expression and the promotion of neutrophil tissue infiltration [7,41]. These observations suggest that IL-1 may play a deleterious role in cerebral ischemia. Studies showing a reduction in infarct size after the administration of IL-1 antagonists or inhibitors provide further evidence of the importance of IL-1 in cerebral ischemia [41,43-49]. The possible harmful mechanisms induced or activated by IL-1 include fever, increased heart rate and arterial blood pressure, enhancement of N-methyl-D-aspartate-mediated injury, proliferation of microglia, release of arachidonic acid, and stimulation of NO synthesis [7,50]. 

Cyclic pentapeptide is a potent inhibitor of a4] l-mediated cell adhesion to CS-1 site and VCAM with IC50 ranging from 2 to 9 pM in cell adhesion assays. Under this background, Ho and Broka reported the synthesis of peptidomimetic tricyclic tetrahydrobenzo [ij] quinolone in 2000 [95]. Palladium-catalyzed alkoxycarb-onylation of aryl triflate was applied and produced the needed intermediate in moderate yield (Scheme 10.20). 

Biological target The 1,2,3-triazole-linked, diphenyl-substituted neoglycoconjugate 1 is a selective inhibitor of human a-l,3-fiicosyltransferase IV (Fuc-T), the enzyme catalysing the final step in the synthesis of oligosaccharides, including the leukocyte and leukaemic cell adhesion molecule, sialyl Lewis X. 

Sunazaka T, Hirose T, Harigaya Y, Takamatsu S, Hayashi M, Komiyama K, Omura S. Relative and absolute stereochemistries and total synthesis of (+)-macrosphelides A and B, potent, orally bioavailable inhibitors of cell-cell adhesion. J. Am. Chem. Soc. 1997 19 10247 10248. 

Sunazuka, T., Hirose, T., Chikaraishi, N., Harigaya, Y., Hayashi, M., Komiyama, K., Sprengeler, P.A., Smith, A.B., and Omura, S. (2005) Absolute stereochemistries and total synthesis of ( )-macrosphelides, potent, orally bioavailable inhibitors of cell-cell adhesion. Tetrahedron, 61, 3789-3803. 

The naturally occurring PP2A inhibitor cytostatin (152), which was isolated from a Streptomyces inhibits the adhesion of B16 melanoma cells to laminin and collagen, displays anti metastatic and cytotoxic activity and induces apoptosis of B16 melanoma cells. The synthesis of the 4S,5S,6S,10S,11S,12S isomer of cyto-... 

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