Recent Advances in Classical and Non-Classical Antifolates as Antitumor and Antiopportunistic Infection Agents: Part I

Abstract

Antifolates that inhibit the key enzymes thymidylate synthase (TS) and dihydrofolate reductase (DHFR) have found clinical utility as antitumor and antiopportunistic agents. Methotrexate {MTX, (1)} and 5-fluorouracil (5-FU) were among the first clinically useful DHFR and TS inhibitors, respectively. The development of resistance to 5-FU, its occasional unpredictable activity and toxicity resulted in the search of novel antifolates. Pemetrexed (4) and raltitrexed (5) specifically inhibit TS, and are clinically useful as antitumor agents. A major mechanism of tumor resistance to clinically useful antifolates is based on their need for polyglutamylation via the enzyme folylpoly-gamma-glutamate synthetase (FPGS). Novel antifolates have been developed that do not need to be polyglutamylated and include plevitrexed (6) and GW1843 (7). Nonclassical antifolates for antitumor and parasitic chemotherapy, such as nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)}, can passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Variations in the structures of antifolates have helped delineate the structural influence on the interaction with TS, DHFR, FPGS, and RFC utilization. The differences in the active site of human and pathogen DHFR have also been exploited. The literature contains excellent reviews on the design and synthesis of antifolates prior to 1996. This two-part review discusses the design, synthesis and structural requirements for TS and DHFR inhibition and their relevance to antitumor and parasitic chemotherapy, since 1996. Monocyclic and 6-5 fused bicyclic antifolates will be discussed in Part I, while 6-6 bicyclic and tricyclic antifolates will be discussed in Part II.

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

“…Antifolates are classic antitumor agents that inhibit key enzymes in DNA synthesis, such as thymidylate synthase and DHFR, whose expression is regulated by E2F-1. One of the initial clinically useful blockers of DHFR was methotrexate (13,14), which is frequently used in the treatment of acute leukemias and a number of solid tumors (15). Although this drug and other antifolate drugs are relevant in the treatment of cancer, drug resistance poses a major obstacle to their effectiveness.…”

Potentiation of Available Antibiotics by Targeting Resistance – An Emerging Trend in Tuberculosis Drug Development

“…Whereas proteins participating in folate metabolism are well known, most current folate antagonists are thought to act on either the biosynthesis or the reduction of folate (Bermingham & Derrick, 2002, Gangjee et al, 2007, 2008. Whereas trimethoprim and folate analogs such as methotrexate inhibit the reduction step through inhibition of dihydrofolate reductases (DHFR), sulfonamides and sulfone drugs are pABA analogs that outcompete pABA in the condensation with the pteridin group, catalyzed by dihydropteroate synthase (DHPS) (Bermingham & Derrick, 2002, Gangjee et al, 2007, 2008.…”

“…The two affected residues are located in the drug binding region of M. tuberculosis DHPS and are highly conserved throughout bacteria and protozoa (Baca et al, 2000). Combined mutations in DHFR and DHPS encoding genes have been known to confer resistance to all available antifolates (Bermingham & Derrick, 2002, Gangjee et al, 2007, 2008. It is important to note that most current knowledge of trimethoprim and sulfonamide resistance comes from studies of bacteria distantly related to M. tuberculosis, and very limited information on mechanisms involved in antifolate resistance is available for mycobacterial species.…”

“…However, in many cases including that of M. tuberculosis, the synergistic effect of trimethoprim on sulfonamides remains questioned and inconclusive (Forgacs et al, 2009, Ong et al, 2010, Suling et al, 1998. In addition, bacterial strains resistant to both trimethoprim and sulfonamides have readily been isolated (Bermingham & Derrick, 2002, Gangjee et al, 2007, 2008. Therefore, novel potentiation approaches targeting resistance mechanisms might be more effective in both potentiating available antifolates and preventing the emergence of resistant strains.…”

Inhibition studies of quinazoline-sulfonamide derivatives against the γ-CA (PgiCA) from the pathogenic bacterium,Porphyromonas gingivalis

“…Quinazolines are 1,3-benzodiazine derivatives representing an important class among heterocyclic compounds of medical, biological, and industrial interest. They attracted the attention of many researchers since the discovery of Thymitaq, Ralitrexed, Gefitinib and Erlotinib as approved anti-tumor drugs in addition to Prazosin, the second-line drug of choice for the management of elevated blood pressure [24][25][26][27] . Here, we test a new series of sulfonamides containing quinazoline scaffolds, recently developed in our laboratories, for their ability to inhibit the PgiCA enzyme.…”