Screening of inhibitors for anchorage-independent tumor cell growth from microbial metabolites and their application in cancer chemotherapy

从微生物次级代谢产物中筛选肿瘤细胞非贴壁依赖性生长的抑制剂。对500株放线菌和100株真菌在液体培养基中进行培养，并对正丁醇提取物进行筛选。一种放线菌和一种真菌对人结肠癌DLD-1细胞的非贴壁生长表现出强的抑制活性。从放线菌发酵液中分离得到一个新的抗肿瘤活性化合物TT 2149-C。经分类学鉴定，该菌株为Streptomyces thermoviolaceus TP-A0648。TT 2149-C是穗霉素的类似物，其作为抗肿瘤抗生素从链霉菌属分离。TT 2149-C对DLD-1细胞的贴壁依赖性生长有抑制作用，抑制IC<50>为29 nM; IC_<50>2为68 nM。TT 2149-C显示出非常强的 ...更多信息 对多种人癌细胞系的IC_（50）为0.1 ~ 120 nm。从真菌Penicillium aurantiogriseum TP-F_（0213）中分离得到一种新的抗肿瘤化合物茴醚。通过对茴香醚双对溴苯甲酸酯的X射线衍射分析，确定其结构为（3β，5α，7β，11β，16β）-16-乙酰氧基-3，7，11-三羟基麦角甾-22-烯-6-酮。对DLD-1细胞的贴壁依赖性生长有抑制作用，<50>IC_40 μM，IC_1.2 μ <50>M。茴香醚的选择性上级优于TT 2149-C。对蛋白激酶、法尼基转移酶和微管蛋白功能没有显示出茴香醚活性。用合成的衍生物研究了茴雌酚的构效关系。3-和7-羟基的乙酰化导致活性损失。3-羟基乙酰化降低了对锚定依赖性生长的毒性，但增强了对非锚定依赖性生长的细胞毒性。对茴香醚的构效关系进行了进一步的研究。少

Inhibitors for anchorage-independent growth of tumor cells were screened from microbial secondary metabolites. Five hundred strains of actinomycetes and one hundred strains of fungi were cultured in liquid medium and the 1-butanol extracts were subjected to the screening. One actinomycete and one fungus showed potent inhibitory activity against the anchorage-independent growth of human colon tumor DLD-1 cells. The active compounds were isolated from the culture broth by chromatography using HPLC analysis and bioassay.From the actinomycete, a novel antitumor compound TT2149-C was isolated. The producing-strain, was identified as Streptomyces thermoviolaceus TP-A0648 by taxonomic studies. TT2149-C is an analog of spicamycin, which was isolated from Streptomyces sp. as an antitumor antibiotic. TT2149-C inhibited the anchorage-independent growth of DLD-1 cells with the IC_<50> of 29 nM whereas it inhibited the anchorage-dependent growth with. the IC_<50> of 68 nM. TT2149-C showed very pote … More nt cytocidal activity against a variety of human cancer cell lines with the IC50 of 0.1 to 120 nM.A novel antitumor compound anicequol was isolated from the fungus Penicillium aurantiogriseum TP-F0213. The structure of anicequol was confirmed as (3β, 5α, 7β, 11β, 16β-16-acetoxy-3,7,11-trihydroxyergost-22-en-6-one by X-ray diffraction of bis-p-bromobenzoate of anicequol. Anicequol inhibited the anchorage-independent growth of DLD-1 cells with the IC_<50> of 1.2 μM whereas it inhibited the anchorage-dependent growth with the IC_<50> of 40 μM. The selectivity of anicequol is superior to that of TT2149-C. Anicequol did not show activity against protein kinases, farnesyl transferase and tublin function. Structure-activity relationship (SAR) of anicequol, was studied using synthetic derivatives. Acetylation of 3-and 7-hydroxy groups resulted in the loss of activity. However, the acetylation of 3-hydroxy group reduced the toxicity to the anchorage-dependent growth but enhanced the cytotoxicity to the anchorage-independent growth. SAR of anicequol will be studied furthermore. Less