There are many connections between CA and cancer; for example, some CA isozymes (CA IX and XII) are predominantly found in cancer cells and not in the normal counterparts (Pastorek et al. 1994; Pastorekova et al. 1997; Chegwidden et al. 2001). Teicher et al. (1993) reported that acetazolamide (4.44) functions as a modulator in anticancer therapies in combination with different cytotoxic agents, such as alkylating agents, nucleoside analogs or platinum derivatives. It was hypothesized that the anticancer effects of acetazolamide (alone or in combination with such drugs) might be due to acidification of the intratumoral environment occurring after CA inhibition, although other mechanisms of action of this drug were not excluded (Treicher et al. 1993). Chegwidden et al. (2001) hypothesized that in vitro inhibition of growth in cell cultures of human lymphoma cells with two other potent, clinically used sulfonamide CAIs, methazolamide (4.48) and ethoxzolamide (4.81), is probably due to the reduced provision of bicarbonate for nucleotide synthesis (HCO3- is the substrate of carbamoyl phosphate synthetase II) as a consequence of CA inhibition.
The development of CAIs possessing potent tumor cell growth inhibitory properties was reported by this group (Supuran and Scozzafava 2000b, 2000c; Scozzafava and Supuran 2000a; Supuran et al. 2001). Such compounds were discovered in a large screening program [in collaboration with the National Institutes of Health (NIH)] of sulfonamide CAIs. Several hundred aromatic/heterocyclic sulfonamides were assessed in vitro as potential inhibitors of growth of a multitude of tumor cell lines, such as leukemia, nonsmall cell lung cancer, ovarian, melanoma, colon, CNS, renal, prostate and breast cancers. The active compounds (most of them nanomolar inhibitors of CA II and CA IV), of types 4.212 to 4.223, belong to both the aromatic and the heterocyclic sulfonamide classes and showed GI50 values (molarity of inhibitor producing a 50% inhibition of tumor cell growth after a 48-h exposure to the drug) in the micromolar range (Supuran and Scozzafava 2000b, 2000c). Better antitumor compounds were then developed by an original strategy, and they incorporated in their molecules N,N-dialkylthiocarbonylsulfenylamino moieties (Scoz-zafava and Supuran 2000a; Supuran et al. 2001). Thus, aromatic/heterocyclic sulfonamides possessing free amino, imino or hydrazino groups of types A-Y (see the tail approach) were transformed to the corresponding N-morpholyl-thiocarbonyl-sulfenyl or N,N-dimethyl/diethyl-thiocarbonylsulfenylamino derivatives 4.224 to 4.226 by reaction with dithiocarbamates in the presence of oxidizing agents (NaClO or iodine).
Sulfonamides of the types 4.224 to 4.226 showed nanomolar affinity for CA II and CA IV, but, more importantly, some of them inhibited the growth of several tumor cell lines at concentrations as low as 10 nM (Scozzafava and Supuran 2000a; Supuran et al. 2001), thus showing a highly increased antitumor efficacy as compared with classical CAIs (acetazolamide, methazolamide) or compounds 4.212 to 4.218.
The antitumor sulfonamide indisulam, E7070 (4.227), is in Phase II clinical trials in Europe and the U.S. as a novel anticancer agent to treat solid tumors (Supuran 2003). This compound is also a very potent inhibitor of many CA isozymes, including CA I, II and IX (unpublished results from our laboratory).
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