Synthesis of the antileukemic agents 5,10-dideazaaminopterin and 5,10-dideaza-5,6,7,8-tetrahydroaminopterin

Taylor, Edward C.; Harrington, Peter J.; Fletcher, Stephen R.; Beardsley, G. Peter; Moran, Richard G.

doi:10.1021/jm00145a012

Cited by 147 publications

(86 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In a collaboration between academic and pharmaceutical sectors designed to develop antifolates which inhibit enzyme targets other than DHFR, E. C. Taylor (Princeton University) and Chuan (Joe) Shih (Eli Lilly) collaborated to synthesize the (6R) diastereomer of 5,10-dideaza THF known as LMX (Taylor et al, 1985;Moran et al, 1989;Mendelsohn et al, 1999) (Fig. 1).…”

Section: Role Of Antifolates In Cancer Therapymentioning

confidence: 99%

“…Interestingly, loss of ATP renders p53 transcriptionally inert such that LMX showed cytotoxic activity independent of p53 status (Bronder and Moran, 2003). LMX showed promising preclinical antitumor activity in vitro and in vivo with assorted tumor models (Taylor et al, 1985;Beardsley et al, 1989;Moran et al, 1989;Mendelsohn et al, 1999). In a phase I clinical trial, LMX caused severe cumulative toxicity, including dose-limiting myelosuppression and mucositis (Ray et al, 1993).…”

Section: Role Of Antifolates In Cancer Therapymentioning

confidence: 99%

See 1 more Smart Citation

The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer

2014

View full text Add to dashboard Cite

This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary folates and appears to be important for transport of folates into the central nervous system. Clinically relevant antifolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antifolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases.

show abstract

Section: Role Of Antifolates In Cancer Therapymentioning

confidence: 99%

Section: Role Of Antifolates In Cancer Therapymentioning

confidence: 99%

The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer

2014

View full text Add to dashboard Cite

show abstract

“…PALA is an unusual case among the cancer chemotherapeutic agents, for even those drugs which inhibit enzyme targets directly and exclusively usually result in downstream DNA strand breaks. Another rare cytotoxic compound that does not induce DNA strand breaks is the antimetabolite 5,10-dideazatetrahydrofolate (DDATHF) (9), the prototypical inhibitor of the first folatedependent enzyme in de novo purine synthesis, glycinamide ribonucleotide formyltransferase (GART) (10 -12). DDATHF and its analogs cause a rapid decline in ATP and GTP pools (11,13,14) and, concomitantly, potent inhibition of cell growth (11,(15)(16)(17)(18).…”

mentioning

confidence: 99%

A Defect in the p53 Response Pathway Induced by de Novo Purine Synthesis Inhibition

Bronder

Moran

2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

p53 is believed to sense cellular ribonucleotide depletion in the absence of DNA strand breaks and to respond by imposition of a p21-dependent G 1 cell cycle arrest. We now report that the p53-dependent G 1 checkpoint is blocked in human carcinoma cell lines after inhibition of de novo purine synthesis by folate analogs inhibitory to glycinamide ribonucleotide formyltransferase (GART). p53 accumulated in HCT116, MCF7, or A549 carcinoma cells upon GART inhibition, but, surprisingly, transcription of several p53 targets, including p21 cip1/waf1 , was impaired. The mechanism of this defect was examined. The p53 accumulating in these cells was nuclear but was not phosphorylated at serines 6, 15, and 20, nor was it acetylated at lysines 373 or 382. The DDATHF-stabilized p53 bound to the p21 promoter in vitro and in vivo but did not activate histone acetylation over the p53 binding sites in the p21 promoter that is an integral part of the transcriptional response mediated by the DNA damage pathway. We concluded that the robust initial response of the p53 pathway to GART inhibitors is not transcriptionally propagated to target genes due to a defect in p53 post-translational modifications and a failure to open chromatin structure despite promoter binding of this unmodified p53.

show abstract

“…The prototypical members of three of these classes are (6R)-5,10-dideazatetrahydrofolate ((6R)-DDATHF, lometrexol) 1 (1), the quinazoline-based compound, ZD-1694 (tomudex) (2), (4 -6), the first folate-dependent enzyme in de novo purine synthesis, ZD-1694 is an inhibitor of thymidylate synthase (2), and MTA has multiple targets within folate metabolism (7). All three of these drugs have been shown to be very active against several animal tumors and also against a spectrum of human carcinoma xenografts (2,(7)(8)(9).…”

mentioning

confidence: 99%

Cellular Folates Prevent Polyglutamation of 5,10-Dideazatetrahydrofolate

Tse

Moran

1998

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Mouse L1210 cell variants were selected for resistance to 5,10-dideazatetrahydrofolate, a potent inhibitor of the first folate-dependent enzyme in de novo purine synthesis, glycinamide ribonucleotide formyltransferase. The drug-resistant phenotype selected was conditional to the folate compound used to support growth: grown on folic acid cells were 400-fold resistant, whereas they were 2.5-fold more sensitive to 5,10-dideazatetrahydrofolate than wild-type L1210 cells when grown on folinic acid. In folic acid-containing media, polyglutamation of 5,10-dideazatetrahydrofolate was markedly reduced, yet folylpolyglutamate synthetase activity was not different from that in parental L1210 cells. Resistance was due to two changes in membrane transport: a minor increase in the K m for 5,10-dideazatetrahydrofolate influx, and a major increase in folic acid transport. Enhanced folic acid transport resulted in an expanded cellular content of folates which blocked polyglutamation of 5,10-dideazatetrahydrofolate.We propose that polyglutamation of 5,10-dideazatetrahydrofolate is limited by feedback inhibition by cellular folates on folylpolyglutamate synthetase, an effect which reflects a mechanism in place to control the level of cellular folates. Although the primary alteration causative of resistance is different from those reported previously, all 5,10-dideazatetrahydrofolate resistance phenotypes result in decreased drug polyglutamation, reflecting the centrality of this reaction to the action of 5,10-dideazatetrahydrofolate.Development of classes of folate antimetabolites inhibitory to target enzymes other than dihydrofolate reductase has offered new therapeutic agents for the treatment of human malignancies, and has also provided new biochemical probes for studying folate metabolism and the linkages between cell proliferation and survival. The prototypical members of three of these classes are (6R)-5,10-dideazatetrahydrofolate ((6R)-DDATHF, lometrexol) 1 (1), the quinazoline-based compound, ZD-1694 (tomudex) (2), and N

show abstract

Synthesis of the antileukemic agents 5,10-dideazaaminopterin and 5,10-dideaza-5,6,7,8-tetrahydroaminopterin

Abstract: Total syntheses from pyridine precursors of 5,10-dideazaaminopterin (1) and 5,10-dideaza-5,6,7,8-tetrahydroaminopterin (2) are described. These compounds exhibit significant in vivo activity against L1210 leukemia that is comparable to that observed with methotrexate.

Cited by 147 publications

References 10 publications

The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer

The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer

A Defect in the p53 Response Pathway Induced by de Novo Purine Synthesis Inhibition

Cellular Folates Prevent Polyglutamation of 5,10-Dideazatetrahydrofolate

Contact Info

Product

Resources

About