Jadomycin B

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Jadomycin B
Category New Products
Catalog number BBF-05722
CAS 149633-99-8
Molecular Weight 549.6
Molecular Formula C30H31NO9
Purity ≥98% by HPLC

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Description

Jadomycin B is an angucyclic natural product produced by Streptomyces venezuelae ISP5230. It exhibits antimicrobial, antitumor activity and inhibits aurora-B kinase and DNA cleaving. It was also shown to be effective against a variety of staphylococci.

Specification

Synonyms 1-(sec-butyl)-12-((4,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-7-hydroxy-5-methyl-8H-benzo[b]oxazolo[3,2-f]phenanthridine-2,8,13(1H,3aH)-trione; 8H-Benzo(b)oxazolo(3,2-f)phenanthridine-2,8,13(1H,3aH)-trione, 12-((2,6-dideoxyhexopyranosyl)oxy)-7-hydroxy-5-methyl-1-(1-methylpropyl)-
IUPAC Name 3-butan-2-yl-19-(4,5-dihydroxy-6-methyloxan-2-yl)oxy-11-hydroxy-9-methyl-5-oxa-2-azapentacyclo[11.8.0.02,6.07,12.015,20]henicosa-1(13),7(12),8,10,15(20),16,18-heptaene-4,14,21-trione
Canonical SMILES CCC(C)C1C(=O)OC2N1C3=C(C4=C2C=C(C=C4O)C)C(=O)C5=C(C3=O)C(=CC=C5)OC6CC(C(C(O6)C)O)O
InChI InChI=1S/C30H31NO9/c1-5-13(3)24-30(37)40-29-16-9-12(2)10-17(32)21(16)23-25(31(24)29)28(36)22-15(27(23)35)7-6-8-19(22)39-20-11-18(33)26(34)14(4)38-20/h6-10,13-14,18,20,24,26,29,32-34H,5,11H2,1-4H3
InChI Key BSBSCJRAEMDCHC-UHFFFAOYSA-N

Properties

Appearance Solid Powder
Antibiotic Activity Spectrum Neoplastics (Tumor)

Reference Reading

1. Identification of JadG as the B ring opening oxygenase catalyzing the oxidative C-C bond cleavage reaction in jadomycin biosynthesis
Keqiang Fan, Guohui Pan, Xiaojing Peng, Jianting Zheng, Wubin Gao, Juan Wang, Weishan Wang, Yue Li, Keqian Yang Chem Biol. 2012 Nov 21;19(11):1381-90. doi: 10.1016/j.chembiol.2012.09.009.
Jadomycin B is a member of atypical angucycline antibiotics whose biosynthesis involves a unique ring opening C-C bond cleavage reaction. Here, we firmly identified JadG as the enzyme responsible for the B ring opening reaction in jadomycin biosynthesis. In vitro analysis of the JadG catalyzed reaction revealed that it requires FMNH(2) or FADH(2) as cofactors in the conversion of dehydrorabelomycin to jadomycin A. The cofactors could be supplied by either a cluster-situated flavin reductase JadY or the Escherichia coli Fre. JadY was characterized as a NAD(P)H-dependent FMN/FAD reductase, with FMN as the preferred substrate. Disruption mutant of jadY still produced jadomycin, indicating that the function of JadY could be substituted by other enzymes in the host. JadG represents the biochemically verified member of an enzyme class catalyzing an unprecedented C-C bond cleavage reaction.
2. Biosynthesis, synthetic studies, and biological activities of the jadomycin alkaloids and related analogues
Charles B de Koning, Kennedy J Ngwira, Amanda L Rousseau Alkaloids Chem Biol. 2020;84:125-199. doi: 10.1016/bs.alkal.2020.02.001. Epub 2020 Mar 9.
The jadomycins are an expanding class of compounds produced from Streptomyces venezuelae, by diverting the normal biosynthesis which provides the antibiotic chloramphenicol. In the presence of amino acids, and either by heat shock, supplementation with ethanol, or when phage SV1 is added to the culture, the formation of substituted jadomycins and benzo[b]phenanthridines can be achieved. The first part of this review provides details of intermediates involved in the biosynthesis of the jadomycins and the related benzo[b]phenanthridines. Both the jadomycins and the benzo[b]phenanthridines share biosynthetic pathways with a large class of naturally occurring compounds known as the angucyclines. The biosynthetic pathways diverge when it is postulated that an intermediate quinone, such as 3-(2-formyl-6-hydroxy-4-methylphenyl)-8-hydroxy-1,4-naphthoquinone-2-carboxylic acid is formed. The quinone then undergoes reactions with amino acids and derivatives in the culture medium to ultimately afford a library of jadomycins and a few benzo[b]phenanthridines. The second part of the review initially details synthetic efforts toward the synthesis of the naturally occurring benzo[b]phenanthridine, phenanthroviridin, and then outlines methods that have been used to assemble a selection of jadomycins. Total syntheses of jadomycin A and B, derived from l-isoleucine, are described. In addition, the synthesis of the aglycon of jadomycins M, W, S, and T is outlined. These four jadomycins were derived from l-methionine, l-tryptophan, l-serine and l-threonine respectively. As a result of these synthetic efforts, the structures of jadomycin S and T have been revised. The third part of the review describes the reported antibacterial and anticancer activities of both the jadomycins and some naturally occurring benzo[b]phenanthridines.
3. Pilot study of jadomycin B pharmacokinetics and anti-tumoral effects in zebrafish larvae and mouse breast cancer xenograft models
Brendan T McKeown, Nicholas J Relja, Steven R Hall, Simon Gebremeskel, Jeanna M MacLeod, Chansey J Veinotte, Leah G Bennett, Leanne B Ohlund, Lekha Sleno, David L Jakeman, Jason N Berman, Brent Johnston, Kerry B Goralski Can J Physiol Pharmacol. 2022 Nov 1;100(11):1065-1076. doi: 10.1139/cjpp-2022-0152. Epub 2022 Aug 19.
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.

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