The expansive library of jadomycins

Abstract

The jadomycin family of natural products was discovered from Streptomyces venezuelae ISP5230 in the 1990s. Subsequent identification of the biosynthetic gene cluster along with synthetic efforts established that incorporation of an amino acid into the polyaromatic angucycline core occurs non-enzymatically. Over two decades, the precursor-directed biosynthetic potential of the jadomycins has been heavily exploited, generating a library exceeding 70 compounds. This review compiles the jadomycins that have been isolated and characterized to date; these include jadomycins incorporating proteinogenic and non-proteinogenic amino acids, semi-synthetic derivatives, biosynthetic shunt products, compounds isolated in structural gene deletion studies, and deoxysugar sugar variant jadomycins produced by deletion or heterologous expression of sugar biosynthetic genes.

Jadomycins: A potential chemotherapy for multi‐drug resistant metastatic breast cancer

“…venezuelae grown in media containing a single amino acid as the nitrogen source selectively produces diverse analogs of the jadomycin molecule. 10 Interestingly, S . venezuelae incorporates amino acids into the jadomycin polyaromatic core through chemical biosynthesis in a non‐enzymatic manner.…”

“…venezuelae incorporates amino acids into the jadomycin polyaromatic core through chemical biosynthesis in a non‐enzymatic manner. 10 , 19 This is an important feature, as over 70 jadomycins are conveniently synthesized in vitro through chemical methods, which facilitates structural diversity around the E‐ring and produces jadomycins with unique pharmacological properties (Figure 2A ). 10 However, the ability to synthesize jadomycin derivatives through the use of selective media is not always achieved in the presence of a single amino acid.…”

“… 10 , 19 This is an important feature, as over 70 jadomycins are conveniently synthesized in vitro through chemical methods, which facilitates structural diversity around the E‐ring and produces jadomycins with unique pharmacological properties (Figure 2A ). 10 However, the ability to synthesize jadomycin derivatives through the use of selective media is not always achieved in the presence of a single amino acid. 20 For example, media containing 3‐ or 4‐(aminomethyl)benzoic acid (3AMBA and 4AMBA) normally inhibits S .…”

“… 16 Jadomycin DT and S both have polar carboxy side chains, which may be responsible for their ability to induce cancer cell death. 10 , 16 Polarity of the side chain is perhaps more important than size, as jadomycin G has one of the smallest side chains but is non‐polar and exhibits little pharmacological activity. 16 Aromatic amino acids also appear to sterically hinder jadomycin interaction with cancer cells, as jadomycin H and Y with histidine and tyrosine groups, respectively, were less efficacious than jadomycins with nonaromatic groups.…”

“…Jadomycins, a group of molecules first isolated in 1991 from the soil bacteria Streptomyces venezuelae ISP5230, have demonstrated promising cytotoxicity against triple‐negative and hormone receptor positive MDR metastatic breast cancer cells, and may therefore be useful as a novel chemotherapy. 6 , 7 , 8 , 9 , 10 Here, we review the current evidence pertaining to jadomycin cytotoxicity in various cancer cell lines, with a specific focus on MDR breast cancer. Our search strategy utilized Google Scholar and the PubMed and Novanet databases, and included the key terms “jadomycin,” “copper dependency,” “reactive oxygen species,” “aurora B kinase,” and “topoisomerase,”.…”