Search

Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11and 16) exhibited potent cell growth inhibition in vitro(GI50: 9 nM and 20 nM). Interestingly, both compounds displayed improved selectivity among different cancer cell lines, in contrast to the natural products antofine and cryptopleurine. Mechanism of action (MOA) studies suggested that R-antofine promotes dysregulation of DNA replication during early S phase, while no similar effects were observed for 11and 15on corresponding replication initiation complexes. Compound 11also showed greatly reduced cytotoxicity against normal cells and moderate antitumor activity against HT-29 human colorectal adenocarcinoma xenograft in mice without overt toxicity. [ABSTRACT FROM AUTHOR]

Nineteen new phenanthrene-based tylophorine analogues with various functional groups on the piperidine moiety were designed, synthesized, and evaluated for in vitro anticancer activity against four human tumor cell lines. Analogues 15and 21showed approximately 2-fold enhanced inhibitory activity as compared with our prior lead compound (PBT-1). Analogues 23and 24with S-and R-configured substituents, respectively, at the piperidine 3′-position exhibited comparable cytotoxicity to that of PBT-1. Furthermore, mechanistic studies to investigate the effects of the new compounds on Akt protein in lung cancer cells and the NF-kB signaling pathway suggested that the compounds may exert their inhibitory activity on tumor cells through inhibition of activation of both Akt and NF-kB signaling pathway. [ABSTRACT FROM AUTHOR]

In a continuing study, we explored how the individual rings in neo-tanshinlactone (1) influence its potent and selective in vitro antibreast cancer activity. Accordingly, we discovered a novel class of antibreast cancer agents, 2-(furan-2-yl)naphthalen-1-ol derivatives, based on an active C-ring opened model compound 5. Further optimization led to 18and 21, which showed decreased cytotoxic potency but better selectivity than neo-tanshinlactone analogue 2. Interestingly, 20showed broad cytotoxicity against human cancer cell lines. [ABSTRACT FROM AUTHOR]

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 24bshowed 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. [ABSTRACT FROM AUTHOR]

Tylophorine and related natural compounds exhibit potent antitumor activities. We previously showed that PBT-1, a synthetic C9-substituted phenanthrene-based tylophorine (PBT) derivative, significantly inhibits growth of various cancer cells. In this study, we further explored the mechanisms and potential of PBT-1 as an anticancer agent. PBT-1 dose-dependently suppressed colony formation and induced cell cycle G2/M arrest and apoptosis. DNA microarray and pathway analysis showed that PBT-1 activated the apoptosis pathway and mitogen-activated protein kinase signaling. In contrast, PBT-1 suppressed the nuclear factor kappaB (NF-κB) pathway and focal adhesion. We further confirmed that PBT-1 suppressed Akt activation accelerated RelA degradation via IκB kinase-α and down-regulated NF-κB target gene expression. The reciprocal recruitment of RelA and RelB on COX-2 promoter region led to down-regulation of transcriptional activity. We conclude that PBT-1 induces cell cycle G2/M arrest and apoptosis by inactivating Akt and by inhibiting the NF-κB signaling pathway. PBT-1 may be a good drug candidate for anticancer chemotherapy. [ABSTRACT FROM AUTHOR]