It is important to pursue function-oriented synthesis (FOS), a strategy for the design of less structurally complex targets with comparable or superior activity that can be made in a practical manner, because compared to synthetic drugs, many biologically relevant natural products possess large and complex chemical structures that may restrict chemical modifications in a structure–activity relationship study. In this account, we describe recent efforts to simplify complex nucleoside natural products including caprazamycins. Considering the structure–activity relationship study with several truncated analogues, three types of simplified derivatives, namely, oxazolidine, isoxazolidine, and lactam-fused isoxazolidine-containing uridine derivatives, were designed and efficiently synthesized. These simplified derivatives have exhibited promising antibacterial activities. A significant feature of our studies is the rational and drastic simplification of the molecular architecture of caprazamycins. This study provides a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria.

Function-oriented synthesis of a class of liponucleoside antibiotics was investigated through rational simplification guided by previous structure–activity relationship studies of caprazamycins and muraymycins to address the issue associated with their molecular complexity. A lactam-fused isoxazolidine scaffold was designed, and a diverse set of lactam-fused isoxazolidines derivatives were constructed by intramolecular 1,3-dipolar cycloaddition of alkenyl nitrones. Several analogues exhibited moderate activity against a range of Gram-positive drug-resistant bacterial pathogens.

The development process for syringolin A analogues having improved proteasome inhibitory and antitumor activity is described. The strategy was to first establish a convergent synthesis of syringolin A using a rare intramolecular Ugi three-component reaction in the last stage of the synthesis, so as to gain access toa set of structure-based analogues. The inhibitory activity of chymotrypsin-like activity of 20S proteasome was largely improved by targeting the S3 subsite of the β5 subunit. Cytotoxic activity was also improved by installing the membrane-permeable substituent. These biological properties are comparable to those of bortezomib, a clinically used first-line proteasome inhibitor.

The development process for syringolin A analogues having improved proteasome inhibitory and antitumor activity is described. The strategy was to first establish a convergent synthesis of syringolin A using a rare intramolecular Ugi three-component reaction in the last stage of the synthesis, so as to gain access toa set of structure-based analogues. The inhibitory activity of chymotrypsin-like activity of 20S proteasome was largely improved by targeting the S3 subsite of the β5 subunit. Cytotoxic activity was also improved by installing the membrane-permeable substituent. These biological properties are comparable to those of bortezomib, a clinically used first-line proteasome inhibitor.