Antitumor Agents 253. Design, Synthesis, and Antitumor Evaluation of Novel 9-Substituted Phenanthrene-Based Tylophorine Derivatives as Potential Anticancer Agents

Abstract

C9-Substituted phenanthrene-based tylophorine derivatives (PBTs) (13-36) were synthesized and evaluated as in vitro anticancer agents against the human A549 lung cancer cell line. Twelve active compounds were further examined against DU-145 (prostate), ZR-751 (breast), KB (nasopharyngeal), and KB-Vin (multidrug resistant KB subline) human cancer cell lines. They showed potent cytotoxic activity against both wild type and matched multidrug resistant KB cell lines, and displayed notable selectivity toward DU-145 (prostate) and ZR-751 (breast) cancer cell lines. The mode of action of this class may be distinctly different from that of other cancer chemotherapeutic compounds. Three PBT analogs were also evaluated in a murine model. Compound 24b showed modest in vivo antitumor activity against human A549 xenograft in nude mice as well as potent in vitro cytotoxic activity, and thus, is a promising anticancer lead compound.

The Antitumor Agent PBT-1 Directly Targets HSP90 and hnRNP A2/B1 and Inhibits Lung Adenocarcinoma Growth and Metastasis

“…Tylophorine belongs to a group of natural plant compounds, the phenanthroindolizidine alkaloids, which have high potency against various cancer cell lines. 3−5 However, trials of tylocrebrine, a positional isomer of tylophorine, had to be discontinued because of adverse effects on the central nervous system (CNS). 6 Molecular pharmacologic studies have sought to design compounds of this class with minimal CNS toxicity.…”

“…8 Because their increased polarity should prevent them from penetrating the blood–brain barrier, these compounds are likely to have little or no CNS toxicity. 3 One of these compounds, phenanthrene-based tylophorine derivative-1 (PBT-1), displayed potent cytotoxic activity against the human lung cancer cell line A549. 3 Its ability to inhibit the growth of human lung cancer cells is mediated through the downregulation of AKT phosphorylation and NF-κB signaling.…”

“…3 One of these compounds, phenanthrene-based tylophorine derivative-1 (PBT-1), displayed potent cytotoxic activity against the human lung cancer cell line A549. 3 Its ability to inhibit the growth of human lung cancer cells is mediated through the downregulation of AKT phosphorylation and NF-κB signaling. 9 Since AKT and NF-κB signaling are known to play important roles in cancer metastasis and drug resistance 10,11 and the invasion and migration abilities of A549 cells have been shown to be suppressed by treatment with Akt inhibitor IV, dominant-negative AKT expression vector, or specific Akt siRNA, 12 this raises the possibility that PBT-1 may inhibit metastasis in lung cancer cells.…”

Antitumor Agents. 289. Design, Synthesis, and Anti-Breast Cancer Activity in Vivo of 4-Amino-2H-benzo[h]chromen-2-one and 4-Amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one Analogues with Improved Water Solubility

“…4,5 A useful approach is to install polar functional groups, such as acidic or basic groups, which can also be converted to salts that have better water solubility. 6,7 …”

“…Previous studies also suggested that compounds with an amino functional group, which can impart higher polarity and be converted to a salt form, exhibited improved water solubility without any loss in the inhibitory potency. 7 Motivated by these results, a series of diamino analogues was designed to improve water solubility and explore the structure-activity relationships (SAR). The anti-mammary epithelial proliferation and apoptosis-promoting activities of the lead compounds was examined with in vivo wild-type and Brca1/p53 mouse mammary models of human breast cancer.…”