4 research outputs found
The Expansive Library of Jadomycins
The jadomycin family of natural products were 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 approaching seventy compounds. This review compiles the jadomycins 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.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author
Isolation of a Post-PKS C-C Branching Jadomycin from S. venezuelae ISP5230 in the presence of 8-aminooctanoic acid
The jadomycin family of natural products were first identified and characterized by Vining and co-workers at Dalhousie University in the 1990s. Herein, we report findings from a recently developed co-amino acid supplementation culture method with S. venezuelae ISP5230 using 8-aminooctanoic acid, where the major natural product was a jadomycin variant omitting an E-ring (1). These results reinforce that the 3a position is susceptible to nucleophilic addition by cellular metabolites in jadomycin biosynthesis when amino acids with which intramolecular cyclization is unfavorable. Further, the cytotoxicity data for several unsubstituted E-ring jadomycins are reported and discussed.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author
Post Polyketide Synthase Carbon–Carbon Bond Formation in Type-II PKS-Derived Natural Products from <i>Streptomyces venezuelae</i>
Polyketide synthase (PKS) derived
natural products are biosynthesized
by head-to-tail addition of acetate and malonate extender units resulting
in linear extended-polyketide chains. Despite the well-documented
structural diversity associated with PKS-derived natural products,
C–C chain branching deviating from the usual linear pattern
is relatively rare. Herein, type-II PKS angucyclic natural products
containing a hemiaminal functionality were identified and proposed
as the parent of a series of C–C-branched analogues. These
C–C linked acetate or pyruvate branching units were located
at the α-positions on the extended polyketide chains of jadomycins
incorporating 3- and 4-aminomethylbenzoic acids. Labeling studies
utilizing [1-<sup>13</sup>C]-d-glucose provided mechanistic
evidence that the C–C bond formation occurred as a result of
a previously unidentified post-PKS processing, additional to the enzymes
encoded within the biosynthetic gene cluster. Selected compounds were
evaluated in cytotoxic or antimicrobial assays
Pilot study of jadomycin B pharmacokinetics and anti-tumoral effects in zebrafish larvae and mouse breast cancer xenograft models
Despite numerous therapeutic options, multidrug resistance (MDR) remains an obstacle to successful breast cancer therapy. Jadomycin B, a natural product derived from Streptomyces venezuelae ISP5230, maintains cytotoxicity in MDR human breast cancer cells. Our objectives were to evaluate the pharmacokinetics, toxicity, anti-tumoral, and anti-metastatic effects of jadomycin B in zebrafish larvae and mice. In a zebrafish larval xenograft model, jadomycin B significantly reduced the proliferation of human MDA-MB-231 cells at or below its maximum tolerated dose (40 µm). In female Balb/C mice, a single intraperitoneal dose (6 mg/kg) was rapidly absorbed with a maximum serum concentration of 3.4 ± 0.27 µm. Jadomycin B concentrations declined biphasically with an elimination half-life of 1.7 ± 0.058 h. In the 4T1 mouse mammary carcinoma model, jadomycin B (12 mg/kg every 12 h from day 6 to 15 after tumor cell injection) decreased primary tumor volume compared to vehicle control. Jadomycin B-treated mice did not exhibit weight loss, nor significant increases in biomarkers of impaired hepatic (alanine aminotransferase) and renal (creatinine) function. In conclusion, jadomycin B demonstrated a good safety profile and provided partial anti-tumoral effects, warranting further dose-escalation safety and efficacy studies in MDR breast cancer models