tylophorine-b and antofine

New water soluble antofine C-13a analogues were designed, synthesized, and evaluated for antiproliferative activity against cancer cells. Particularly, (-)-(R)-13a-hydroxymethylantofine ((-)-(R)-4b) demonstrated notable growth inhibition against a panel of human cancer cell lines. This growth inhibition was associated with the arrest of the cell cycle in the G0/G1 phases and suppression of mTOR signaling in human lung A549 cancer cells. Compound (-)-(R)-4b also overcame paclitaxel-resistance in human lung cancer cells (A549-Pa) by suppressing P-glycoprotein expression. Furthermore, compound (-)-(R)-4b significantly inhibited the tumor growth of A549 and A549-Pa xenografts in a nude mouse model, which suggests it is a promising novel antitumor agent with sufficient aqueous solubility.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; G1 Phase Cell Cycle Checkpoints; HCT116 Cells; HEK293 Cells; Humans; Indoles; Lung Neoplasms; Mice; Mice, Nude; Phenanthrolines; Signal Transduction; Stereoisomerism; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Water

Due to their limited natural abundance and significant biochemical effects, we synthesized the alkaloids (+/-)-antofine (1a), (+/-)-deoxypergularinine (1b), and their dehydro congeners (2 and 3) starting from the corresponding phenanthrene-9-carboxaldehydes. We also evaluated their in vitro cytotoxic activity. Compounds 1a and 1b showed significant potency against various human tumor cell lines, including a drug-resistant variant, with EC(50) values ranging from 0.16 to 16ng/mL. Structure-activity correlations of these alkaloids and some of their synthetic intermediates were also ascertained. The non-planar structure between the two major moieties, phenanthrene and indolizidine, plays a crucial role in the cytotoxic activity of phenanthroindolizidines. Increasing the planarity and rigidity of the indolizidine moiety significantly reduced potency. A methoxy group at the 2-position (1a) was more favorable for cytotoxic activity than a hydrogen atom (1b).

Topics: Alkaloids; Bromides; Cell Line, Tumor; Chlorides; Drug Resistance, Neoplasm; Humans; Indoles; Indolizines; Isoquinolines; KB Cells; Phenanthrolines

Due to the profound cytotoxicities and interesting biochemical aspects, phenanthroindolizidine alkaloids have received an attention as potential therapeutic leads. To define the features of the molecule that are essential for cytotoxicity, we have synthesized and evaluated a series of phenanthroindolizidine alkaloid, antofine, analogues with different substituents on the phenanthrene ring. The systematic structure activity relationship studies elucidate the essential functional group requirement of phenanthrene ring, providing the basis for further development of phenanthroindolizidine alkaloids.

Topics: Antineoplastic Agents; Cell Line, Tumor; Humans; Indoles; Phenanthrolines; Structure-Activity Relationship