englerin-b and Kidney-Neoplasms

Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on ¬over 500 well characterized cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A. Genetic experiments demonstrate that TRPC4 expression is both necessary and sufficient for englerin A induced growth inhibition. Englerin A induces calcium influx and membrane depolarization in cells expressing high levels of TRPC4 or its close ortholog TRPC5. Electrophysiology experiments confirmed that englerin A is a TRPC4 agonist. Both the englerin A induced current and the englerin A induced growth inhibition can be blocked by the TRPC4/C5 inhibitor ML204. These experiments confirm that activation of TRPC4/C5 channels inhibits tumor cell line proliferation and confirms the TRPC4 target hypothesis generated by the cell line profiling. In selectivity assays englerin A weakly inhibits TRPA1, TRPV3/V4, and TRPM8 which suggests that englerin A may bind a common feature of TRP ion channels. In vivo experiments show that englerin A is lethal in rodents near doses needed to activate the TRPC4 channel. This toxicity suggests that englerin A itself is probably unsuitable for further drug development. However, since englerin A can be synthesized in the laboratory, it may be a useful chemical starting point to identify novel modulators of other TRP family channels.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; HEK293 Cells; Humans; Indoles; Kidney Neoplasms; Mice; Mice, Nude; Piperidines; Rats; RNA Interference; RNA, Small Interfering; Sesquiterpenes, Guaiane; Transfection; TRPC Cation Channels

The chlorinated englerins (3-9) were isolated from Phyllanthus engleri and shown to selectively inhibit the growth of renal cancer cells. The compounds were shown to be extraction artifacts produced by exposure to chloroform decomposition products during their isolation. The most active compound, 3, was synthesized from englerin A (1).

Topics: Antineoplastic Agents, Phytogenic; Drug Screening Assays, Antitumor; Humans; Hydrocarbons, Chlorinated; Kidney; Kidney Neoplasms; Molecular Structure; National Cancer Institute (U.S.); Phyllanthus; Sesquiterpenes, Guaiane; Stereoisomerism; Tanzania; United States

Englerins A and B are guaiane sesquiterpenes that were isolated from the bark of Phyllanthus engleri, a plant indigenous to east Africa. The englerins consist of a 5-6-5 fused tricyclic structure with an ether bridge and two ester-bearing stereogenic centers, including a highly unusual glycolate residue. Englerin A is a potent and selective inhibitor of the growth of six human renal cancer cell lines. We report herein an efficient, eight-step synthesis of englerin A that leverages simple carbonyl-enabled carbon-carbon bond formations. Our route is amenable to the production of a diverse series of analogues for structure-function studies and determination of the mode of action of these natural products.

Topics: Antineoplastic Agents, Phytogenic; Humans; Kidney Neoplasms; Phyllanthus; Sesquiterpenes, Guaiane

Topics: Antineoplastic Agents; Cell Line, Tumor; Humans; Inhibitory Concentration 50; Kidney Neoplasms; Molecular Structure; Sesquiterpenes, Guaiane; Stereoisomerism; Structure-Activity Relationship

Total synthesis of englerin A, a recently reported sesquiterpenoid exhibiting potent and selective growth inhibition against renal cancer cell lines, has been accomplished. The successful strategy featured a [5 + 2] cycloaddition reaction to cast the seven-membered oxabicyclic key intermediate in both racemic and optically active forms. Synthetic (+/-)-englerin A, (+/-)-englerin B, (+/-)-englerin B acetate, a hydroxy acetate, a tert-butyldimethylsilyl ether, and hydrogenated (+/-)-englerin A (31) were tested for their cytotoxicity against a selected panel of cancer cell lines, and the results are path-pointing to more focused structure-activity relationship studies.

Topics: Acetates; Antineoplastic Agents; Cell Line, Tumor; Esters; Humans; Inhibitory Concentration 50; Kidney Neoplasms; Sesquiterpenes, Guaiane; Stereoisomerism