Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target.

MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.

Synthesis of capuramycin and its analogues via a Ferrier-type I reaction and their biological evaluation.

The total synthesis of capuramycin (1), which is a promising anti-tubercular antibiotics, has been accomplished using Ferrier-type I reaction as a key step. This total synthesis is an alternative approach to the synthesis of capuramycin and its analogues. The 3'-O-demethyl analogue (2), which exhibits an equivalent antibacterial activity as capuramycin (1) against Mycobacterium smegmatis and Mycobacterium avium, is suggested to have potential as a lead structure of capuramycin analogues because 2 is more accessible from a synthetic view point.

Design, synthesis and conformation-activity relationship analysis of LNA/BNA-type 5'-O-aminoribosyluridine as MraY inhibitors.

It is important to understand and control the biologically active conformation in medicinal chemistry. Muraymycins and caprazamycins, which are strong inhibitors of MraY, are promising antibacterial agents with a novel mode of action. Focusing on a sugar puckering and a dihedral angle ϕ of the uridine moiety of these natural products, LNA/BNA-type 5'-O-aminoribosyluridine analogues, whose puckering of the ribose moiety are completely restricted to the N-type, were designed and synthesized as simplified MraY inhibitors. Their conformation-activity relationship was further investigated in details. The conformation-activity relationship analysis investigated in this study could be a general guideline for simplification and rational drug design of MraY inhibitory nucleoside natural products.

Synthesis and in vitro evaluation of thiododecaborated α, α- cycloalkylamino acids for the treatment of malignant brain tumors by boron neutron capture therapy.

Boron-neutron capture therapy (BNCT) is an attractive technique for cancer treatment. As such, α, α-cycloalkyl amino acids containing thiododecaborate ([B12H11](2-)-S-) units were designed and synthesized as novel boron delivery agents for BNCT. In the present study, new thiododecaborate α, α-cycloalkyl amino acids were synthesized, and biological evaluation of the boron compounds as boron carrier for BNCT was carried out.

Biological evaluation of dodecaborate-containing L-amino acids for boron neutron capture therapy.

To develop a boron carrier for practical purposes, new boron-containing amino acids with an undecahydro-closo-dodecaboranylthio ([(10)B(12)H(11)S](2-)-) unit in the side chain of the α-amino acid have already been designed and synthesized. In the present paper, cytotoxicity, the incorporation amounts into tumor cells, and the tumor cell killing effects of these compounds were elucidated to evaluate their usefulness as boron carriers. Furthermore, the microdistribution of the amino acids in tumor cells was established.

Synthesis of optically active dodecaborate-containing L-amino acids for BNCT.

A convenient and simple synthetic method of dodecaboratethio-L-amino acid, a new class of tumor-seeking boron carrier for BNCT, was accomplished from S-cyanoethylthioundecahydro-closo-dodecaborate (S-cyanoethyl-(10)BSH, [(10)B(12)H(11)](2-)SCH(2)CH(2)CN) and bromo-L-α-amino acids by nearly one step S-alkylation. An improved synthesis of S-cyanoethyl-(10)BSH, a key starting compound for S-alkylation, was also performed by Michael addition of (10)BSH with acryronitrile in high yield. Four kinds of new dodecaboratethio-L-amino acids were obtained in optically pure form without the need for any optical resolution.