Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?

Abstract

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.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…FOS applications were reviewedr ecently; [181,182,183] hence, only selected examples are given below.I np articular,e nediyne drugs were designed aroundd ynemicin A, which was isolated from Micromonospora chersina in the mid-1980s. This NP has Scheme5.To tal synthesiso fEpoBand its analogues (KI = key intermediate).…”

Simplification of Natural β-Carboline Alkaloids to Obtain Indole Derivatives as Potent Fungicides against Rice Sheath Blight

“…Of these compounds, indole (7, EC 50 = 25.56 µg/mL) displayed superior fungicidal activity, and was 7-fold as potent as validamycin A (EC 50 = 183.00 µg/mL). Additionally, it can be seen quite clearly that the structural changes in general were detrimental to activity and no favorable substitution could be found for the 2-or 3-position, even after extensive probing with a variety of diverse groups (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). These findings implied that indole was a potent fungicidal template for further modification and derivatization.…”

“…In the quest for novel fungicidal agents, natural bioactive products have been and remain an excellent source of novel structure and serve as templates and inspiration for fungicides [8,9]. However, natural bioactive products are often victims of several deficiencies such as paucity or difficulty of obtainment from natural sources, as some natural product leads possess rather large, complex, or labile chemical structures which are difficult to obtain quantitatively by chemical synthesis, and complex, or labile chemical structures which are difficult to obtain quantitatively by chemical synthesis, and most are not optimally ideal for direct use because of these weak activities [10]. Therefore, structural modification or simplification of active lead compounds from natural products has proven to be a successful way to discover fungicides with new modes of action, such as strobilurins fungicides.…”

Molecular modeling studies of pseudouridine isoxazolidinyl nucleoside analogues as potential inhibitors of the pseudouridine 5ʹ‐monophosphate glycosidase

“…[8,11] The genes encoding these proteins are absent from the genomes of man and other mammals; normally, this nucleoside is present in human urine, and its concentration is increased in tumor-bearing patients. [21][22][23][24][25][26][27][28][29] In our research group, isoxazolidine replacement has also been employed for Ψ modification, leading to the development of the isoxazolidinyl-C-nucleosides 1-3 ( Figure 1). [13,14] The majority of nucleoside analogs consist of modifications of the natural substrates in the heterocyclic base and/or the sugar moiety.…”

“…[15] Isoxazolidine ring has been extensively used as a simplified alternative to the nucleoside sugar. [21][22][23][24][25][26][27][28][29] In our research group, isoxazolidine replacement has also been employed for Ψ modification, leading to the development of the isoxazolidinyl-C-nucleosides 1-3 ( Figure 1). [30] In light of the mechanism of the Ψ cleavage, [11] the peculiar reactivity of the isoxazolidine ring could prevent the ring-opening process, thus inhibiting the enzyme activity.…”