Structural studies on bioactive compounds. 8. Synthesis, crystal structure and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line

Griffin, Roger J.; Meek, M. A.; Schwalbe, Carl H.; Stevens, Malcolm F. G.

doi:10.1021/jm00131a009

Cited by 20 publications

(26 citation statements)

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“…The target analogues were readily prepared from Pyrimethamine (Pyr) [26, 27]. Briefly, direct nitration of Pyr under standard condition afforded m-nitropyrimethamine (MNP) in near quantitative yield.…”

Section: Methodsmentioning

confidence: 99%

New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study

Tommasino

Gambardella

Buoncervello

et al. 2016

J Exp Clin Cancer Res

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BackgroundThe antimalarial drug Pyrimethamine has been suggested to exert an antitumor activity by inducing apoptotic cell death in cancer cells, including metastatic melanoma cells. However, the dose of Pyrimethamine to be considered as an anticancer agent appears to be significantly higher than the maximum dose used as an antiprotozoal drug.MethodsHence, a series of Pyrimethamine analogs has been synthesized and screened for their apoptosis induction in two cultured metastatic melanoma cell lines. One of these analogs, the Methylbenzoprim, was further analyzed to evaluate cell-cycle and the mechanisms of cell death. The effects of Methylbenzoprim were also analyzed in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model.ResultsLow dose of Methylbenzoprim was capable of inducing cytotoxic activity and a potent growth-inhibitory effect by arresting cell cycle in S-phase in melanoma cells. Methylbenzoprim was also detected as powerful antineoplastic agents in SCID-mouse although used at very low dose and as a single agent.ConclusionsOur screening approach led to the identification of a “low cost” newly synthesized drug (methylbenzoprim), which is able to act as an antineoplastic agent in vitro and in vivo, inhibiting melanoma tumor growth at very low concentrations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0409-9) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study

Tommasino

Gambardella

Buoncervello

et al. 2016

J Exp Clin Cancer Res

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“…Griffin et al [124] previously reported the synthesis of lipophilic PYR derivatives as potent inhibitors of mammalian DHFR. Among a series of compounds evaluated for antitumor inhibition, the dimethyltriazenyl-substituted pyrimethamine analog 34 (Fig.…”

Section: Pyr Analogsmentioning

confidence: 99%

Dihydrofolate Reductase as a Target for Chemotherapy in Parasites

Gangjee¹,

Kurup²,

Namjoshi³

2007

CPD

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Opportunistic infections are known to cause morbidity and mortality in immunocompromised individuals. In addition, serious infections due to several parasites are also known to affect the quality and duration of life in normal individuals. The importance of dihydrofolate reductase (DHFR) in parasitic chemotherapy arises from its function in DNA biosynthesis and cell replication. DHFR catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), an essential cofactor in the biosynthesis of thymidylate monophosphate (dTMP). Inhibition of DHFR leads to a deficiency of dTMP since DHF cannot be recycled, and thus causes inhibition of cell growth. Methotrexate (MTX) and aminopterin (AMT) were among the first known classical inhibitors of DHFR. Trimethoprim (TMP) and pyrimethamine (PYR) are among the first known non classical inhibitors of DHFR. TMP and PYR are selective but weak inhibitors of DHFR from several parasitic organisms and coadministration of sulfonamides is required to provide synergistic effects for clinical utility. Unfortunately, the side effects associated with sulfa drugs in this combination often result in cessation of therapy. Trimetrexate (TMQ) and piritrexim (PTX) are two potent non classical inhibitors, neither of which exhibit selectivity for pathogen DHFR and must be used with host rescue. However, the current combination therapy suffers from high cost, in addition, several mutations have been reported in the active site of parasitic DHFR rendering the infections refractive to known DHFR inhibitors. The selectivity of TMP is a hallmark in the development of DHFR inhibitors and several efforts have been made to combine the potency of PTX and TMQ with the selectivity of TMP. Thus the structural requirements for DHFR inhibition are of critical importance in the design of antifolates for parasitic chemotherapy. Structural requirements for inhibition have been studied extensively and novel agents that exploit the differences in the active site of human and parasitic DHFR have been proposed. This review discusses the synthesis and structural requirements for selective DHFR inhibition and their relevance to parasitic chemotherapy, since 1995.

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“…However, as the crystal structure of the diaminopyrimidine-DHFR complex was solved in 1989, [161] researchers at Abbott undertook docking studies between compound 67 and DHFR with the aim of enhancing the selectivity of their compounds. They compared the binding mode of compound 67 with DHFR and the supposed binding mode of the same compound with GHS-R1a.…”

Section: 4-diaminopyrimidinesmentioning

confidence: 99%

Recent Developments in Ghrelin Receptor Ligands

et al. 2007

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The 28-amino acid peptide ghrelin is a neuroendocrine hormone synthesized primarily in the stomach. It stimulates growth hormone secretion and appetite, thus promoting food intake and body-weight gain. The pharmacological properties of this peptide are mediated by the growth hormone secretagogue receptor type 1a (GHS-R1a). Given its wide spectrum of biological activities, it is evident that the discovery of ghrelin and its receptor has opened up many perspectives in the fields of neuroendocrine and metabolic research and has had an influence on such fields of internal medicine as gastroenterology, oncology, and cardiology. It is therefore increasingly likely that synthetic, peptidyl, and nonpeptidyl GHS-R1a ligands, acting as agonists, partial agonists, antagonists, or inverse agonists, could have both clinical and therapeutic potential. This review summarizes the various types of GHS-R1a ligands that have been described in the literature and discusses the recent progress made in this research area.

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Structural studies on bioactive compounds. 8. Synthesis, crystal structure and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line

Cited by 20 publications

References 2 publications

New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study

New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study

Dihydrofolate Reductase as a Target for Chemotherapy in Parasites

Recent Developments in Ghrelin Receptor Ligands

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