LL-D49194 antibiotics, a novel family of antitumor agents. Taxonomy, fermentation and biological properties.

Abstract

A novel family of antitumor antibiotics, designated LL-D49194, was isolated from the fermentation broth of an actinomycete strain identified as Streptomyces vinaceus-drappus. LL-D49194 a1 and p2 were active against Gram-positive and inactive against Gram-negative bacteria in vitro. The p± component was not active against either Gram-positive or Gram-negative bacteria. These antibiotics exhibited significant in vivo activities against several murine tumors, albeit with differing potencies.In the course of our search for novel antitumor agents produced by microorganisms, a culture designated LL-D49194was isolated from a soil sample and was found to produce a new family of antitumor compounds (Fig. 1). This paper describes the taxonomy of the producing culture, fermentation and biological activities of these agents. Materials and Methods MicroorganismCulture LL-D49194 was isolated from a soil sample collected in La Encanada, Peru. This culture was Fig. 1. Chemical structures of LL-D49194 al5 px and f}2.

A comprehensive review of glycosylated bacterial natural products

“…18 The C-4- O -α-L-trioxacarcinose A moiety ( 122 ) is common to all trioxacarcin glycosides, including the monoglycosidic trioxacarcins A1 (DC-45-A1) and E, the diglycosidic trioxacarcins (A, B, D, F), gutingimycin, 1282 and the triglycosidic LL-D49194 (α1, β1, β2, e and w 1). 1283 Additional C16- O -glycosylation with a mono-( 122 ) or disaccharide (fragment I ) side chain was observed in the LL-D49194 analogs while additional C-13- O -glycosylation with α-L-trioxacarcinose B ( 103 ) or its corresponding keto-reduced trioxacarcinose B ( 323 ), was observed in trioxacarcins A–D, F and gutingimycin. Sugar 323 of trioxacarcin C and its keto-form 103 have also been found appended to the anthracycline antibiotics isoquinocycline A and kosinostatin (Section 4.1), respectively.…”

Resistance-Guided Mining of Bacterial Genotoxins Defines a Family of DNA Glycosylases

“…2C and D and Table S3 ). Almost half ( n = 32; 47%) localize to clusters resembling those producing known DNA-damaging agents, including AZB ( n = 5), LL-D4919α1 (LLD, n = 6), HED ( n = 4), ficellomycin/vazabitide A ( n = 5), and C-1027/leinamycin ( n = 2) ( 12 , 16 – 18 , 40 , 41 ). In addition, several other clusters are related to potential DNA-damaging agents on the basis of a reactive epoxide functional group in the natural product, including angucycline-like molecules ( n = 4) herboxidiene and asukamycin.…”

“…Streptomyces produce a wide variety of DNA alkylating and oxidizing agents that have antimicrobial and antitumor properties. Spirocyclopropylcyclohexadienones (duocarmycin A and SA, yatakemycin, and CC-1065) ( 9 , 10 ), pluramycins (pluramycin A, hedamycin, and altromycin) ( 11 – 13 ), anthracycline glycosides (trioxacarcin A and LL-D49194α1) ( 14 – 16 ), and the leinamycin family ( 17 ) contain a single reactive group that covalently modifies purine nucleobases to form a broad spectrum of bulky alkyl-DNA monoadducts. Streptomyces also produce bifunctional alkylating agents that react with nucleobases on both DNA strands to create interstrand cross-links (ICLs).…”

Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues

“…The trioxacarcinose A residue is common to many of the naturally occurring trioxacarcins, including the monoglycoside DC-45-A1, the bisglycoside trioxacarcin A, and the trisglycoside LL-D49194α1 (Figure 1). 12 We elected to explore initial couplings with 1- O -acetyl trioxacarcinose A ( 3 , Figure 2), which is available in multi-gram amounts by a short and practical sequence. 13 We found that when a mixture of diol 2 (1 equiv), glycosyl donor 3 (2 equiv, a 1:12 mixture of α- and β-anomers, respectively), and powdered 4-Å molecular sieves in dichloromethane at −40 °C was treated with boron trifluoride etherate (1.0 equiv) as promoter the α-monoglycoside 4 was formed in 79% yield (23 mg).…”