Camporidines A and B: Antimetastatic and Anti-inflammatory Polyketide Alkaloids from a Gut Bacterium of the Carpenter Ant, Camponotus kiusiuensis

Abstract

Chemical studies of gut bacteria of the carpenter ant Camponotus kiusiuensis led to the discovery of two new alkaloids, camporidines A and B (1-2), from Streptomyces sp. STA1 strain. The structures of 1 and 2 were established as new polyketide alkaloids bearing a piperidine-cyclopentene-epoxide 6/5/3 tricyclic system based on NMR spectroscopic and mass spectrometric analysis. The relative configurations of the camporidines were determined by their 1H-1H NOESY/ROESY and 1D NOE NMR correlations. The experimental ECD spectra of 1 and 2 were compared with their calculated ECD spectra to assign their absolute configurations. Camporidine A (1) showed antimetastatic activity by suppression of cell invasion against the metastatic breast cancer cell line MDA-MB-231 and showed an anti-inflammatory effect by suppressing nitric oxide (NO) production induced by lipopolysaccharide (LPS). In addition, the putative biosynthetic gene cluster of the camporidines was identified, and the biosynthetic pathway of the camporidines was proposed based on bioinformatic analysis of the full genome of Streptomyces sp. STA1 strain. Camporidines A and B (1-2) could be biosynthesized by a modular type I PKS containing an AT (acyl transferase) domain that accepts an unusual extender unit, which becomes the (C1-C6) hexyl side chain. The post-PKS modification enzymes were predicted to perform an amination and an oxidation along with spontaneous Schiff base formation and generate the unique piperidine-cyclopentene-epoxide 6/5/3 tricyclic framework.

갈색발왕개미의 장에서 분리한 Streptomyces 속 균주 연구를 통해 두 개의 신규 alkaloid계열 물질인 camporidine A와 B를 발견하였다. Camporidine의 구조는 NMR과 Mass spectrometric data를 기반으로 하여 piperidine-cyclopentene-epoxide로 이루어진 6/5/3 삼중환 형태를 포함한 polyketide alkaloid 물질임을 규명하였다. Camporidine의 relative configuration은 1H-1H NOESY/ROESY 과 1D NOE NMR correlations 을 통해 결정하였다. 물질의 실제 측정된ECD spectrum과 calculated ECD spectrum의 비교를 통해 물질의 입체 구조를 결정하였다. Camporidine A는 유방암세포주 (MDA-MB-231)의 cell invasion을 억제하는 암전이 억제 활성과 LPS에 의해 유도되는 NO의 생성을 억제하는 항염증 활성이 관찰되었다. Camporidine의 생합성 유전자로 추정되는 gene cluster를 발견하였고 STA1 균주의 전체 유전자 분석을 통해 camporidine의 생합성 경로를 제안하였다. Camporidine은hexyl chain(C1-C6)이 되는 특정 extender unit을 데려오는 AT domain을 포함하는 type 1 PKS module을 통한 생합성을 예측하였다. Post-PKS modificiation에 관여하는 유전자들을 통해 amination, oxidation과 함께 spontaneous Schiff base formation이 일어나 특이한 piperidine-cyclopentene-epoxide 6/5/3 삼중환 구조가 생성될 것을 예측하였다.