ABSTRACT
The natural products colchicine and combretastatin A-4 are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI50 = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC50 = 1.1 µM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent that may prove useful for the treatment of cancer.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Bibenzyls/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Organophosphates/chemical synthesis , Organophosphates/pharmacology , Tubulin/metabolism , Animals , Antineoplastic Agents/chemistry , Bibenzyls/chemistry , Colchicine/pharmacology , Drug Screening Assays, Antitumor , Humans , Indoles/chemistry , Inhibitory Concentration 50 , Male , Mice , Molecular Structure , Organophosphates/chemistry , Prodrugs/pharmacology , Prostatic Neoplasms/drug therapy , Stilbenes , Structure-Activity Relationship , Tubulin/drug effectsABSTRACT
In the crystal structure of the title compound, C(32)H(39)NO(7)Si, all geometric parameters fall within experimental error of expected values. The analysis of molecular-packing plots reveals an infinite two-dimensional linear array running parallel to the b axis, formed by one N[bond]H...O intermolecular hydrogen-bonding interaction. Several potential C[bond]H...O interactions are also present.
ABSTRACT
Combretastatin A-4 disodiumphosphate (CA4P), a prodrug formulation of the natural product combretastatin A-4 (CA4), is currently in clinical investigation for the treatment of cancer. In vivo, CA4P is rapidly enzymatically converted to CA4, a potent inhibitor of tubulin polymerization (IC(50)=1-2 microM), and rapidly causes bloodflow shutdown in tumor tissues. A variety of alkyl and aryl di- and triesters of CA4P have been synthesized and evaluated as potential CA4 prodrugs and/or stable CA4P analogues.