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Abstract

Several amides of 3-(3',6'-dioxo-2',4'-dimethylcyclohexa-1',4'-diene)-3,3- dimethylpropionic acid (2) have been synthesized and tested as model redox-sensitive pro-prodrugs of amines. The reduction of these model pro-prodrugs generated hydroxy amide intermediates 4a-4h, the lactonization of which resulted in amine release. The rates of lactonization of 4a-4h were investigated at pH 7.4 and 37 degrees C. The half-lives for appearance of the product lactone 1a from these intermediates were found to range from 1.4 to 3.4 min. With such rapid lactonization rates, it is believed that reduction will be the rate-limiting step in the two-step conversion of the pro-prodrug to the amine.

Synthesis of Bioreductive Esters from Fungal Compounds

“…Quinone delivery systems containing a trimethyl lock have been designed to release toxic moieties selectively and preferentially under reductive/hypoxic conditions [5][6][7][8][9] (Fig. 2).…”

“…5,6) The TDDS was a substituted benzoquinone, which can also attach to any drug of interest via an ester or amide linker. [5][6][7][8][9] The conformational constraint in the quinone-containing promoiety was created by the presence of the gem-dimethyl group on the propionic acid spacer linking the drug and the promoiety; and the adjacent methyl group on the quinone ring ("trimethyl lock"). Upon reductive activation, the quinone was converted to its hydroquinone.…”

“…The trimethyl lock-containing structure has been reported to undergo bioreductive activation with rate of reaction giving potential specific delivery of many types of model compounds such as amines, amino acids, peptides, alcohol, fluorophores and other anticancer agents. 7,9,[10][11][12][13][14][15][16][17][18][19] Various substituents on the benzoquinone ring with different electronic properties such as a methyl-substituted benzoquinone were reported to enhance reductase enzyme selectivity and stability of the bioreductive promoiety, while redox properties govern the rate of release of the potent drug. 5,6) Therefore, a methyl-substituted benzoquinone containing a trimethyl lock was selected as a template for the design of a new bioreductive agent from fungal cytotoxic compounds.…”

“…Structure elucidation was confirmed by using IR, HR-MS and NMR. 1 5,[7][8][9] N-Bromosuccinimide (NBS) 0.3 g (1.7 mmol) was dissolved in 30 ml of water. Lactone solution was prepared by dissolving 0.3 g (1.3 mmol) of lactone in 45 ml of acetonitrile.…”

“…4). 5,[7][8][9]21) Preussomerin G Ester (7) and Preussomerin I Ester (8) Quinone propionic acid (53 mg, 0.2 mmol) was dissolved in dry dichloromethane and reacted with preussomerin G or preussomerin I (0.05 mmol) under nitrogen gas. 4-(N,N-dimethylamino)pyridine (DMAP) (0.04 mmol) was added into reaction mixture followed by N,NЈ-dicyclohexylcarbodiimide (DCC) (0.26 mmol) in dry dichloromethane solution.…”