Preparation and biological evaluation of novel leucomycin analogs derived from nitroso Diels–Alder reactions

Abstract

A series of 10,13-disubstituted 16-membered macrolides was synthesized using nitroso Diels–Alder reactions of leucomycin A7. Despite the extensive constituent functionalities in leucomycin, the hetero cycloaddition reactions proceeded in a highly regio- and stereoselective fashion. Subsequent chemical modifications of the nitroso cycloadducts, including N–O bond reduction, were also conducted. Most leucomycin derivatives retained antibiotic profiles similar to leucomycin A7, and, in contrast to leucomycin itself, several exhibited moderate antiproliferative and cytotoxic activity.

Nitroso Diels–Alder (NDA) reaction as an efficient tool for the functionalization of diene-containing natural products

“…The interest was directed towards the creation of an extended library of analogs and the study of their biological activity. 149 …”

Functionalisation of Macroheterocycles with Preserving and Changing Their Sizes

“…a heteroreaction with nitroso dienophiles was applicable for synthesis of some 10,13-disubstituted 16-membered macrolides (103 a-i) from the antibiotic leucomycin A7 (102). [67] Despite wide functionalities of the latter, heterocycloaddition proceeded highly regioand stereoselectively:compounds (103a-i) were obtained as a sole isomer. As demonstrated in the carried out experiments, 2-nitrosopyridines (104a-i) were efficient dienophiles with selective sensitivities to electron and space structures of macrolide (102) with the diene system, which is probably related to their asymmetry.…”

“…and show anticancer activity. Thus, the generation of macrocyclic structure (67) happens upon spontaneous cyclization by the intramolecular Wittig-Horner reaction of compound (68) that is an oxidation product of acyclic precursor (69) (Scheme 17). The introduction of the epoxide ring into macrocycle (67) was carried out in two steps.…”

16‐Membered Macrolide Lactone Derivatives Bearing a Triazole‐Functionalized Arm at the Aglycone C13 Position as Antibacterial and Anticancer Agents

“…[5,6] The most frequent modifications of leucomycins at the saccharides attached to the aglycone and within it have been:e therification [7] and esterification of hydroxy groups, [8] reductivea mination of the aldehyde, [9] epoxidation of the dienef ragment, and formation of carbamates [10] or nitroso cycloadducts. [11] From our earlier studies it is known that eliminationo fa cetate from the b-position of aglycone slightly improves antibacterial potency. [12,13] Published data regarding the role of the aldehyde group in antibacterial potencya re contradictory.O noneh and, it has been reported that absence of the aldehyde group decreases antibacteriala ctivity by~100-to 1000-fold, whereas other reports claim that replacement of the aldehyde with small substituents sustain the antibacterial activity of leucomycins.…”