Synthesis of a key intermediate of novel galbonolide analogues via efficient construction of a conjugated diene system.

The development of an efficient synthetic method enabled multi-gram synthesis of a key intermediate, which is useful for the modification at the C6-functional group of galbonolide analogues. The structure of a key intermediate including a conjugated diene was afforded by Horner-Emmons reaction, alkylation of Weinreb amide with alkyl lithium and a subsequent Wittig reaction.

Synthesis and antifungal activity of novel 14-membered benzomacrolides, as galbonolide analogues.

Asymmetric total synthesis of benzene analogues of galbonolide, a 14-membered antifungal macrolide, possessing a benzene ring instead of a conjugated diene structure, was achieved starting from chiral 1-aryl-1-propanol obtained by enzyme-catalyzed kinetic resolution with high enantioselectivity. Representatively, a method for the introduction of a methylthio and chloride function at the vinyl position was also established. The resulting analogues unfortunately exhibited very little antifungal potency in comparison with galbonolide A.

Novel galbonolide derivatives as IPC synthase inhibitors: design, synthesis and in vitro antifungal activities.

A series of novel galbonolide derivatives having a modified methyl enol ether moiety were prepared in total synthetic procedures and evaluated for their in vitro antifungal activities. The antifungal activity was labile to modification of the enol ether functionality and almost all of the modified compounds lacked the activity except for the analogue with an introduction of a methylthio group at the C-6 position, which retained a modest antifungal potency against Cryptococcus neoformans.

Development of an orexin-2 receptor selective agonist, [Ala(11), D-Leu(15)]orexin-B.

Investigation of L-alanine and D-amino acid replacement of orexin-B revealed that three L-leucine residues at the positions of 11, 14, and 15 in orexin-B were important to show selectivity for the orexin-2 receptor (OX(2)) over the orexin-1 receptor (OX(1)). L-Alanine substitution at position 11 and D-leucine substitution at positions 14 and 15 maintained the potency of orexin-B to mobilize [Ca(2+)](i) in CHO cells expressing the OX(2), while their potency for the OX(1) was significantly reduced. In combined substitutions, we identified that [Ala(11), D-Leu(15)]orexin-B showed a 400-fold selectivity for the OX(2) (EC(50)=0.13nM) over OX(1) (EC(50)=52nM). [Ala(11), D-Leu(15)]orexin-B is a beneficial tool for addressing the functional roles of the OX(2).

Structure--activity relationships of 1beta-methyl-2-(5-phenylpyrrolidin-3-ylthio)carbapenems.

Structure--activity relationship studies of 1beta-methyl-2-[(3S,5R)-5-(4-aminomethylphenyl)pyrrolidin-3-ylthio]carbapenems, especially those pertaining to the relationship between antibacterial activity and side-chain structure were conducted. These studies suggested that the trans-(3S,5R)-5-phenylpyrrolidin-3-ylthio side-chain and the aminomethyl group at the 4-position of the phenyl ring play a key role in enhancing the antibacterial activity against the MRSA and Pseudomonas aeruginosa strains. In particular, the basicity of a substituent at the 4-position of the phenyl ring were shown to greatly contribute to the antibacterial activity against MRSA and methicillin-resistant Staphyloccocus epidermidis strains. In contrast, the amidine group was shown to lead to potent antibacterial activity against P. aeruginosa strains comparable to that of imipenem, however, a good correlation between the basicity of the 4-substituent and antipseudomonal activity was not observed. In conclusion, the 4-aminomethyl or methylaminomethyl group on the phenyl ring was the best substituent for antipseudomonal activity.

Synthesis of the side chain of a novel carbapenem via iodine-mediated oxidative cyclization of (1R)-N-(1-aryl-3-butenyl)acetamide.

A (2R,4S)-trans-disubstituted pyrrolidine ring system was constructed by employing iodine-mediated oxidative cyclization of (1R)-N-[1-(4-bromophenyl)-3-butenyl]acetamide 3 as a key step. The resulting diastereomeric mixture of (2R)-2-aryl-4-acetoxypyrrolidine 4 was stereoselectively converted to the side-chain of a novel ultrabroad-spectrum carbapenem 1, via (2R,4R)-2-aryl-4-hydroxypyrrolidine 7.

A new class of type I protein geranylgeranyltransferase (GGTase I) inhibitor.

Replacement of the thiol groups in 1, a potent and highly selective Candida albicans GGTase I inhibitor discovered through screening, with an imidazole ring was achieved by using solid phase synthesis. A non-thiol compound, 7, was found as a representative of a new class of potent C. albicans GGTase I inhibitor with high selectivity against human GGTase I.