Targeted Discovery of Pentaketide Ansamycin Aminoansamycins A–G

Abstract

Ansamycins are a class of macrolactams with diverse bioactivities, characterized by the unique 3-amino-5-hydroxybenzoic acid moiety. In this study, the ansamycin gene cluster aas in Streptomyces sp. S35 was activated by the constitutive coexpression of two pathway-specific regulator genes aas1 and aas10, and seven novel pentaketide ansamycin aminoansamycins A–G (1–7) were identified. Compound 4 with better antiproliferative activity indicated that the anthranilate analogues are probably promising building blocks for the production of unnatural ansamycins with improved activity.

Structural diversity and biological relevance of benzenoid and atypical ansamycins and their congeners

“…The most active derivative, 30 decorating with an anthranilate motif, revealed quite potent antiproliferative activities (IC 50 s ¼ 7-10 mM). 124 The absence of the anthranilate or AHBA motifs at C(9) (29) decreased potency at least by 2-fold or even contributed to the loss of activity, similarly to the oxidation of the ansamycin core (32,33).…”

“…S35, isolated from soil (Kunming, Yunnan, China). 124 The AasD hydroxylase takes part in the biosyntheses of 29–33 , which is analogous to Nam7 , active in the neoansamycins biosynthesis. Ansamycins 30–33 contain nonproteinogenic AHBA and anthranilate motifs attached to the C(9) position of their ansa chains (Fig.…”

“…Fig. 38 Semisynthetic benzoquinone-C 15 analogs of GDM, 91 (17-DMAG) and 92 (17-AAG) with an extra introduced substituents at C(19)of the core or with the reduced(123) or oxidized(124,125) the core or oxygenated double bond within the ansa bridge(127,128).…”

New Hygrocins K–U and Streptophenylpropanamide A and Bioactive Compounds from the Marine-Associated Streptomyces sp. ZZ1956

“…However, the first maytansines found in plants [ 4 ] are now known to be produced by the interplay amongst bacteria in the root system [ 5 ]. It was reported that nearly 300 ansamycins have been identified from natural sources [ 6 ] and more and more ansamycins continue to be reported, such as the recently described olimycins from the ovmO -inactivated mutant strain Streptomyces olivaceus SCSIO T05 [ 7 ] and ansaseomycins from a heterologous mutant strain of Streptomyces seoulensis [ 8 ]. The ansamycins exhibit diverse biological activities, such as antibacterial (naphthomycin A, rifamycin, rubradirin and streptovaricin A), anticancer (ansamitocins P-3, ansatrienins A, geldanamycin, mitomycin C, saliniketals A and B), lipoxygenase inhibitory (tetrapetalones A and B) and antiviral (divergolide O) activities [ 1 , 9 ].…”

Scalable Total Syntheses of (±)-Catellatolactams A and B

“…In recent years, Lu and co-workers continuously isolated and elucidated an array of structurally novel pentaketide ansamycins named microansamycins A–I and aminoansamycins A–G through a gene activation approach (Figure ). Quite recently in 2022, Igarashi and co-workers reported the isolation of three novel ansamacrolactams from the culture extract of the genus Catellatospora , a rare actinomycete . However, the poor accessibility of these materials severely limited further and systematic biological screening.…”