Phenanthroindolizidine-based tylophora alkaloids have been reported to have potential antitumor, anti-immuno and anti-inflammatory activity. The structure-activity relationships of a series of tylophora alkaloids were studied to guide future drug design. Our results indicate that although these compounds are structural analogs, their potency of cytotoxicity, selectivity against NF-κB signaling pathway, and their inhibitory effects against protein and nucleic acid synthesis are different. Because they do not have an identical spectrum of targets, the studied compounds are structural, but may not be functional analogs.
KeywordsTylophora alkaloids; Structure; activity relationship; Protein; DNA and RNA synthesis Tylophora alkaloids originate from various plants of the Asclepiadaceae family, such as Tylophora, that are native of India and Southeast Asia. 1 They have antitumor, 2-6 antiinflammatory, 7 anti-arthritis, 8 and anti-lupus activity in vivo. 9 Due to their diverse and potent pharmacological actions, they continue to be targets for synthesis, modification, structureactivity relationship (SAR) studies since their first isolation in 1935. 10 Their molecular mechanisms of action of antitumor and anti-inflammatory activity include: inhibitory effect on protein synthesis 2 and nucleic acid synthesis, 2,11 inhibitory effect on RNA transcription which are controlled by cyclic AMP response elements (CREs), activator protein-1 (AP-1) sites, and NF-κB binding sites, 6 and ability to suppress the expression of a subset of proteins, such as cyclin D1, cyclin B1 and CDK4. 12 Tylocrebrine, a positional isomer of tylophorine, was found in clinical trials to have intolerable central nervous system (CNS) side effects. To *Corresponding author. Yung-Chi Cheng: tel.: +1-203-785-7118; fax: +1-203-785-7129; e-mail: E-mail: yccheng@yale.edu. Note: Yung-Chi Cheng is a fellow of the National Foundation for Cancer Research. † These authors contributed equally to this work.Supplementary data Supplementary data associated with this article (Synthesis of phenanthrene-based tylophorine derivatives described in Scheme 1, synthesis of tylophora alkaloids exemplified in Scheme 2, IC 50s of the inhibitory effect of tylophora alkaloids and PBTs against endogenous NF-κB, CRE, AP-1 and GRE mediated transcription in HepG2 cells listed in Table S1) can be found, in the online version, at doi: xxxxxxx.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. offset such CNS side effects, a series of phenanthrene-based tylophorine derivatives (PBTs) with increased polarity was synthesized to limit the crossin...
