Merocyclophanes A and B, antiproliferative cyclophanes from the cultured terrestrial Cyanobacterium Nostoc sp.

Abstract

The cell extract of a cultured terrestrial Nostoc sp. (UIC 10062), obtained from a sample collected at Grand Mere State Park in Michigan, displayed antiproliferative activity against the HT-29 human colon cancer cell line. Bioactivity-guided fractionation of the cell extract, combined with LC-MS analysis, led to the isolation of two cyclophanes, named merocyclophanes A and B (1 and 2). Their structures were determined by various spectroscopic techniques including HRESIMS, and 1D and 2D NMR analyses. The stereoconfiguration was assigned on the basis of X-ray crystallographic and CD analyses. The structures of merocyclophanes A and B (1 and 2) established a hitherto unknown [7.7]paracyclophane skeleton in nature, as characterized by α-branched methyls at C-1/14. Merocyclophanes A and B (1 and 2) displayed antiproliferative activity against the HT-29 human colon cancer cell line with IC50 values of 3.3 and 1.7 µM, respectively.

Carbamidocyclophanes F and G with anti-Mycobacterium tuberculosis activity from the cultured freshwater cyanobacterium Nostoc sp.

“…The absolute configurations were established by comparison of the CD spectrum of 1 to that of nostocyclophanes A–D, cylindrocyclophane A 4 and merocyclophanes A and B. 4,7,8 The negative Cotton effects at 215 nm (Δε −3.72) and 284 nm (Δε −2.85) were similar to those observed for nostocyclophanes A–D, cylindrocyclophane A 4 and merocyclophanes A and B, suggesting the same absolute configuration. Therefore, we submit that the absolute configurations at C-1 and C-14 are “ R ”, while C-7 and C-20 are “ S ”.…”

“…These cyclophanes exhibited wide range of biological activities including antimicrobial, antiproliferative and proteasome inhibitory activities. 5–8 Isotope feeding experiments revealed a unique polyketide biosynthetic pathway in the formation of [7.7]paracyclophane skeleton. 9 In the recent communication by Nakamura et al, the biosynthesis of cylindrocyclophane has been analyzed in detail.…”

Discovery of Anticancer Agents of Diverse Natural Origin

“…A key aspect of our group interactions is the prioritization of in vitro- active crude extracts for subsequent activity-guided purification (17, 18). Cytotoxicity assays using selected cancer cell lines are conducted currently mainly at our biological testing core component at UlC [for example, see (54–56)], with some solid tumor and leukemia cancer cell line testing also having been carried out at OSU [for example, see (54, 57, 58)]. Selected target-based in vitro bioassays that have been conducted for the program project include activation of nuclear factor κB (NFκB) (56, 59), mitochondrial transmembrane potential (MTP) (60), and semaphorin 3B assays (61).…”

Merocyclophanes C and D from the Cultured Freshwater Cyanobacterium Nostoc sp. (UIC 10110)

“…A triplet at δ H 3.47 (H-30) was identified as unique to the 1 H spectra of 1 as compared to the published 1 H NMR spectrum of 3 . 15 The triplet integrated to two protons and the chemical shift suggests the presence of an adjacent oxygen. Additionally, the aliphatic terminal methyl group (triplet at δ H 0.83) only integrated to three protons in 1 ; whereas, this triplet integrated to six protons in the symmetrical 3 .…”