Pteridine-sulfonamide conjugates as dual inhibitors of carbonic anhydrases and dihydrofolate reductase with potential antitumor activity.
Recent evidences suggest that cancer treatment based on combination of cytostatic and conventional chemostatic therapeutics, which are usually cytotoxic, can provide an improved curative option. On the sequence of our previous work on methotrexate (MTX) derivatives, we have developed and evaluated novel MTX analogues, containing a pteridine moiety conjugated with benzenesulfonamide derivatives, thus endowed with the potential capacity for dual inhibition of dihydrofolate reductase (DHFR) and carbonic anhydrases (CA). These enzymes are often overexpressed in tumors and are involved in two unrelated cellular pathways, important for tumor survival and progression. Their simultaneous inhibition may turn beneficial in terms of enhanced antitumor activity. Herein we report the design and synthesis of several diaminopteridine-benzenesulfonamide and -benzenesulfonate conjugates, differing in the nature and size of the spacer group between the two key moieties. The inhibition studies performed on a set of CAs and DHFR, revealed the activities in the low nanomolar and low micromolar ranges of concentration, respectively. Some inhibitors showed selectivity for the tumor-related CA (isozyme IX). Cell proliferation assays using two tumor cell lines (the non-small cell lung carcinoma, A549, and prostate carcinoma, PC-3) showed activities only in the millimolar range. Nevertheless, this fact points out the need of improving the cell intake properties of these new compounds, since the general inhibitory profiles revealed their potential as anticancer agents.
Marques
Sérgio M
SM
Instituto Superior Técnico, Centro de Química Estrutural, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
Enyedy
Eva A
EA
Supuran
Claudiu T
CT
Krupenko
Natalia I
NI
Krupenko
Sergey A
SA
Santos
M Amélia
MA
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D008958:Models, Molecular; D011621:Pteridines / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D011621:Pteridines; D013449:Sulfonamides; D013762:Tetrahydrofolate Dehydrogenase; D002256:Carbonic Anhydrases