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  • Author: M. PRADA x
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Abstract

We make a survey of results published by the authors about the backward and forward unilateral weighted shift operators in Kóthe spaces, the so-called generalized derivation and integration operators, extending well-known results for spaces of analytic functions.

Abstract

The serpin plasminogen activator inhibitor type-1 (PAI-1), as the primary physiological inhibitor of both urokinasetype (uPA) and tissuetype (tPA) plasminogen activator, plays an important role in the regulation of the fibrinolytic system as well as in extracellular remodeling in both physiological and pathophysiological processes. In plasma as well as in the extracellular matrix PAI-1 binds to vitronectin (Vn), an interaction that affects the function of both proteins. As PAI-1/Vn interaction has a significant regulatory function in fibrinolysis, thrombolysis, and cell adhesion in cancer spread, there is a strong interest in defining the binding sites on PAI-1 and Vn as the basis of a rational design of novel drugs that may modulate PAI 1/Vnmediated effects. In this minireview, we give an overview on the approaches to define the Vn binding site of PAI-1 and vice versa. Although in the case of PAI-1 the region around αhelix E and αhelix F of PAI 1 has been demonstrated to be important for its interaction with Vn, the precise location of the Vnbinding region has not completely been resolved. The major highaffinity PAI-1 binding region of Vn is localized within the Nterminal somatomedin B (SMB) domain of Vn. There are indications for at least one other lowaffinity PAI-1 binding site in the Cterminal region of Vn, which seems to be involved in the formation of larger PAI-1/Vn complexes.

The fatty acids (±)-2-methoxy-6Z-heptadecenoic acid, (±)-2-methoxy-6-hepta-decynoic acid, and (±)-2-methoxyheptadecanoic acid were synthesized and their inhibitory activity against the Leishmania DNA topoisomerase IB enzyme (LdTopIB) determined. Both 2-OMe-17:1 fatty acids were synthesized from 4-bromo-1-pentanol, the olefinic fatty acid in 10 steps and in 7 % overall yield, while the acetylenic fatty acid in 7 steps and in 14 % overall yield. The 2-OMe-17:0 acid was prepared in 6 steps and in 42 % yield from 1-hexa-decanol. The 2-OMe-17:1 acids inhibited LdTopIB, with the acetylenic acid displaying an EC50 = 16.6 ± 1.1 μM, but the 2-OMe-17:0 acid did not inhibit LdTopIB. The (±)-2-methoxy-6Z-heptadecenoic acid preferentially inhibited LdTopIB over the human TopIB enzyme. Unsaturation seems to be a prerequisite for effective inhibition, rationalized in terms of weak intermolecular interactions between the active site of LdTopIB and either the double or triple bonds of the fatty acids. Toxicity toward Leishmania donovani promastigotes was also investigated, resulting in the order acetylenic > olefinic > saturated with the (±)-2-methoxy-6-heptadecynoic acid displaying an EC50 = 74.0 ± 17.1 μM. Our results indicate that α-methoxylation decreases the toxicity of C17:1 fatty acids toward L. donovani promastigotes, but improves their selectivity index.