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Cispentacin as a Chemical Lead Structure - Interaction ofb-Amino Acids with Natural a-Amino Acid-processing Systems

For cispentacin 91, a metabolite of Bacillus cereus, antifungal activity has been described for the free b-amino acid; this is remarkable for such a simple molecule [137]. The anti-Candida activity of 91 [138] initiated a chemistry program aimed at finding derivatives with superior (oral) efficacy for the treatment of yeast infections (Scheme 1.5.14) [10]. This lead optimization yielded the synthetic methylene derivative BAY 10-8888/PLD-118 92 that acts by a dual mode of action. First, 92 is accumulated in yeast cells by active transport via permeases, specific for branched-chain a-amino acids (e.g. L-Ile). Second, the isoleucyl-tRNA is specifically inhibited, leading to inhibition of protein synthesis and cell growth [10]. In contrast, active transport and inhibition of protein synthesis of natural cispentacin 91 seems to be correlated with the corresponding enzymes specific for L-Pro (and not L-Ile) [138].

This example illustrates how b-amino acids might generally interfere with natural a-

lead optimization h2n co2h h2n co2h cispentacin (91) synthetic from Bacillus cereus BAY 10-8888/PLD-118 (92)

(accumulation via (accumulation via L-Ile transporters)

L-Pro permeases)

Scheme 1.5.14. Natural cispentacin 91 as the chemical lead for BAY 10-8888/PLD-118 92.

amino acid processing systems (e.g. active transport, protein biosynthesis). So far little work has been published on the general biological properties of b-amino acids, e.g. their physicochemistry and pharmacokinetics (e.g. data on absorption, distribution, metabolism, and excretion - ADME).

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The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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