Design, synthesis, and biological evaluation of tumor-selective vascular disrupting agents, water-soluble amino acid prodrug conjugates, and bioreductively activatable prodrug conjugates targeting tumor hypoxia.
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Selective targeting of tumor cells in comparison to healthy cells is vital in order to increase drug efficacy and reduce side effects to cancer patients. The underlying morphological and physiological differences between vasculature feeding healthy tissue versus tumor bearing tissue provides an opportunity to selectively target tumor vasculature as a promising therapeutic option for cancer treatment. Combretastatin A-1 (CA1) and combretastatin A-4 (CA4) are members of a family of inhibitors of tubulin polymerization which functions as tumor-selective vascular disrupting agents (VDAs). The success of clinical trials involving the phosphate prodrugs of CA1 and CA4 (CA1P and CA4P respectively) inspired the design, synthesis, and biological evaluation of structurally related benzosuberene analogues as potent VDAs. A phenolic benzosuberene analogue (referred to as KGP18) and its amino congener (referred to as KGP156) emerged as potential preclinical candidates because of their robust cytotoxicity (sub-nM to pM) against selected human cancer cell lines in vitro, and excellent tubulin inhibitory capabilities. A series of benzosuberene based analogues were synthesized in order to expand the relationship of structure to function in this class of anti-cancer agents. Also, a series of tri- and pentafluoro substituted amino-based combretastatin analogues were synthesized. In an effort to discover new VDAs with improved water solubility and bioavailability, various amino-acid producing conjugates (AAPCs) of potent amino-based combretastatin analogues were synthesized. The corresponding water-soluble hydrochloride salts of these AAPCs were investigated for their ability to be cleaved by the leucine aminopeptidase (LAP) enzyme through a collaborative effort with the Trawick Research Group (Baylor University). The glycinamide hydrochloride salt 2' CA4-amine were cleaved quantitatively by LAP, however only partial cleavage was evident for their serinamide and bis-serinamide counterparts. Since hypoxia is regarded as a hallmark of most solid tumors, a series of hypoxia-activated prodrugs [referred to as bioreductively activated producing onjugates (BCAPs)] of CA1 were synthesized regioselectively. These CA1-BAPCs are capable if being reduced by one or two-electron reductases, principally NAD(P)H cytochrome p450, cleaving the bioreductive trigger and releasing the cytotoxic drug in the hypoxic tumor microenvironment. A new and efficient synthetic methodology was explored to generate three nitrothiophene triggers from a common starting material.