The Ammosamides: Structures of Cell Cycle Modulators from a Marine‐Derived Streptomyces Species

Abstract

From the ocean: Ammosamides A (1) and B (2) were isolated from a marine‐derived Streptomyces species collected in the Bahamas. The structures of these chlorinated tricyclic pyrroloquinoline alkaloids were solved using X‐ray crystallographic techniques. Ammosamide A (1) was shown to contain an unusual thio‐γ‐lactam ring. Both metabolites show specific nanomolar cytotoxicity against selected cancer cell lines.

Design, Synthesis, and Biological Evaluation of Potent Quinoline and Pyrroloquinoline Ammosamide Analogues as Inhibitors of Quinone Reductase 2

“…1-3 All three natural products are thought to modulate tubulin and actin dynamics through myosin binding. 2,4 The administration of a fluorescent ammosamide B conjugate to HCT-116 cells results in the depolymerization of microtubules and an increase in actin filaments, and histological staining is consistent with the binding of the conjugate to several myosin families. 4 …”

“…20 In addition, the ammosamides were originally isolated by cytotoxicity-guided (HCT-116) fractionation, further suggesting that the present series of compounds could be cytotoxic. 2 The compounds were therefore submitted to the NCI panel of 60 human cancer cell lines for cytotoxicity evaluation. 29-31 As documented in Table 3, all of the compounds were surprisingly non-cytotoxic at a concentration of 10 μM.…”

Biosynthetic Pathway Connects Cryptic Ribosomally Synthesized Posttranslationally Modified Peptide Genes with Pyrroloquinoline Alkaloids

“…(Gomez-Escribano and Bibb, 2012, 2014) Cultures of S. coelicolor M512-pCAP01/ amm yielded ammosamides A and B (Figure 3) with 3–4 fold higher production (17 mg each) than the native producer, CNR-698. (Hughes et al, 2009) We further observed after only two days of growth the production of large quantities of ammosamide C ( 3 ), the reduced precursor to A and B. Although ammosamide C is only a minor component of ethyl acetate extracts from 12-day cultures, the liquid chromatography mass spectrometry (LCMS) analysis of aqueous aliquots from both pCAP01/ amm and CNR-698 cultures revealed that ammosamide C is the predominant product of the amm pathway ( Figure S1 ).…”

“…CNR-698. (Hughes et al, 2009) As the ammosamides share the same core structural features of lymphostin (Figure 1), they provide a unique opportunity to explore pyrroloquinoline alkaloid biosynthesis in a distinct genomic context. Herein we show that the marine bacteria-derived pyrroloquinoline alkaloids lymphostin and the ammosamides are derived from a highly non-canonical biosynthetic pathway that more closely resembles the genetic features of ribosomally synthesized, post-translationally modified peptide (RiPP) natural products.…”

Chasing the treasures of the sea — bacterial marine natural products

“…The latter showed broad cytotoxicity in the NCI 60 cell line panel, in addition to considerable selectivity against leukemia and melanoma cell lines. The ammosamides A (8) and B (9), derived from a deep-sea sediment sample Streptomyces strain collected in the Bahamas (20), are chlorinated tricyclic pyrroloquinoline alkaloids, structurally related to the microbial and sponge metabolites lymphostin and batzelline A, respectively. The slow conversion of the thioamide in 8 to the amide in 9 upon standing on air suggests a non-enzymatic formation of the latter in the natural producer.…”