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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