Structure-based design, synthesis, and evaluation of Bcl-2/Mcl-1 dual inhibitors.

Based on our previously reported Bcl-2/Mcl-1 dual inhibitor 4-thiomorpholinyl-2-cyano-3-amidinophenalenone (A1) that simultaneously occupies the p2 and p4 hydrophobic pockets of Bcl-2 and Mcl-1, we optimized molecules with different bond angles of the groups extending to the p4 pocket and bulky hydrophobic groups to explore p2. Research on structure-activity relationship resulted in a new derivative B4 that is capable of occupying both the p2 and p4 more deeply and completely than A1, with Ki values determined by fluorescence polarization assay (FPAs) improving to 0.31 µM for Bcl-2 and 0.16 µM for Mcl-1. Furthermore, B4 exhibited selective lethality on cancer cells over normal cells. It showed stronger apoptosis induction than (-)-gossypol on a Bcl-2/Mcl-1-dependent cancer cell line and killed an Mcl-1-dependent cell line which is resistant to ABT-199 treatment.

Pyridone-containing phenalenone-based photosensitizer working both under light and in the dark for photodynamic therapy.

Photosensitizer attracts great attentions and has potential applications in cancer treatment. We developed here a novel pyridone-containing phenalenone-based (PPN-PYR) photosensitizer with excellent singlet oxygen generating ability. Upon light irradiation, PPN-PYR can produce singlet oxygen and transform to its endoperoxide form which in turn release singlet oxygen via thermal cycloreversion at dark. The ability of PPN-PYR to generate reactive oxygen species (ROS) in cell culture and induce corresponding apoptosis both at dark and under light was demonstrated. The efficient PDT performance of PPN-PYR was further verified on cancer cell in vitro. Our study indicate that PPN-PYR can alleviate tumor hypoxia problem and enhance the availability of intermittent photodynamic therapy.

A novel turn-on fluorescent probe for selective sensing and imaging of glutathione in live cells and organisms.

We synthesized six 1-oxo-1H-phenalene-2,3-dicarbonitrile (OPD)-based probes with various leaving groups using an arylthioether linker and for the first time identified the probe O-NH2 capable of highly selective detection of glutathione over cysteine/homocysteine in vitro and in vivo based on an aromatic nuclear substitution reaction (SNAr) mechanism. The fluorescence of the probe O-NH2 was quenched because of the photoinduced electron transfer (PET) process, but switched on by a glutathione-triggered specific recognition reaction between the probe O-NH2 and glutathione. The recognition mechanism for glutathione was explored and verified by theoretical calculations and ESI-MS analysis. Using O-NH2 as the probe, the GSH fluorescence images were demonstrated in HeLa cells and the intracellular GSH levels in different imatinib-resistant K562 tumor cells were firstly determined. Further, O-NH2 was utilized to detect glutathione in D. magna and zebrafish embryos. The combined results indicate that O-NH2 can be applied as an effective tool for detecting glutathione in biological investigations.

Unusual Nitrogenous Phenalenone Derivatives from the Marine-Derived Fungus Coniothyrium cereale.

The new phenalenone metabolites 1, 2, 4, and 6 were isolated from the marine-derived endophytic fungus Coniothyrium cereale, in addition to the ergostane-type sterol (3) and entatrovenetinone (5). Compounds 1 and 2 represent two unusual nitrogen-containing compounds, which are composed of a sterol portion condensed via two bonds to phenalenone derivatives. Compound 6, which contains unprecedented imine functionality between two carbonyl groups to form a oxepane -imine-dione ring, exhibited a moderate cytotoxicity against K562, U266, and SKM1 cancer cell lines. Moreover, molecular docking studies were done on estrogen receptor α-ligand binding domain (ERα-LBD) to compounds 1 and 2 to correlate with binding energies and affinities calculated from molecular docking to the anti-proliferative activity.

Diarylamines incorporating hexahydrophenalene or octahydrobenzoheptalene as retinoid X receptor (RXR)-specific agonists.

Selective ligands for retinoic acid receptors (RARs) and for retinoid X receptors (RXRs) are required for both biological studies and therapeutic purposes. We have synthesized a series of diarylamines incorporating hexahydrophenalene or octahydrobenzoheptalene as a hydrophobic moiety and examined their activities towards RARs and RXRs. Most of these compounds showed agonistic activity towards RXRs, but were inactive towards RARs. These RXR-specific ligands showed synergistic activity in RARα,ß ligand-induced terminal differentiation of leukemia cell line HL-60.

Design, synthesis and structure­activity relationship studies of morpholino-1H-phenalene derivatives that antagonize Mcl-1/Bcl-2.

We report herein characteristic studies of Mcl-1 and Bcl-2 dual inhibitors. It was found that a protruding carbonyl group forming hydrogen bond with R263 plays a predominant role compared with the hydrophobic group that occupies the p2 pocket. A series of dual inhibitors representing different parts of the morpholino-1H-phenalene were designed, synthesized and evaluated.