Dual Inhibitors of Thymidylate Synthase and Dihydrofolate Reductase as Antitumor Agents:  Design, Synthesis, and Biological Evaluation of Classical and Nonclassical Pyrrolo[2,3-<i>d</i>]pyrimidine Antifolates

Gangjee, Aleem; Jain, Hiteshkumar D.; Phan, Jaclyn; Lin, Xin; Song, Xiaohong; McGuire, John J.; Kisliuk, Roy L.

doi:10.1021/jm058276a

Cited by 44 publications

(50 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Being a building unit of DNA and RNA, pyrimidine derivatives were found to be associated with a variety of chemotherapeutic effects including antimicrobial [6 -10], antitubercular [11], antifungal [12], antimalarial [13], and antiviral [14,15] activities. Furthermore, pyrimidine-containing compounds were reported to contribute to a variety of anticancer potentials including antitumor [16], antineoplastic [17], antiproliferative [18,19], thymidylate synthase and dihydrofolate reductase inhibitory [20], angiogenesis inhibiting [21], and cyclin-dependent kinase inhibitory [22] activities. Interest in the chemotherapeutic activity of pyrimidines stemmed from the early success of some pyrimidine-based antimetabolites such as 5-flurouracil, carmofur, 5-azauracil, cytarabine, and gemcitabine as potential antineoplastic agents [23].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Some Novel Polysubstituted Pyrimidine Derivatives as Potential Antimicrobial and Anticancer Agents

Rostom

Ashour

Razik

2009

Archiv der Pharmazie

View full text Add to dashboard Cite

Synthesis and evaluation of the antimicrobial and cytotoxic activity of two series of polysubstituted pyrimidines comprising the thioether functionality and other pharmacophores, reported to contribute to various chemotherapeutic activities are described. All newly synthesized compounds were subjected to in-vitro antibacterial and antifungal screening. Out of the compounds tested, 18 derivatives displayed an obvious inhibitory effect on the growth of the tested Gram-positive and Gram-negative bacterial strains, with special effectiveness against the Gram-positive strains. Compounds 1, 2, 6, 7, 9, 10, 11, 21, and 24 revealed remarkable broad antibacterial spectrum profiles. Among those, compounds 1, 2, 6, 7, 9, and 24 exhibited an appreciable antifungal activity against C. albicans. Compound 2 proved to be the most active antimicrobial member identified here as it showed twice the activity of ampicillin against B. subtilis and the same activity of ampicillin against M. Luteus and P. aeruginosa together with a moderate antifungal activity. Further, eleven analogs were evaluated for their in-vitro cytotoxic potential utilizing the standard MTT assay against a panel of three human cell lines: breast adenocarcinoma MCF7, hepatocellular carcinoma HePG2, and colon carcinoma HT29. The obtained data revealed that six of the tested compounds 1, 3, 7, 12, 13, and 15 showed a variable degree of cytotoxic activity against the tested cell lines at both the LC(50) and LC(90) levels. Compound 7 proved to be the most active cytotoxic member in this study with special effectiveness against the colon carcinoma HT29 and breast cancer MCF7 human cell lines for LC(50 )and LC(90). Thus, compounds 1 and 7 could be considered as possible dual antimicrobial-anticancer agents.

show abstract

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Some Novel Polysubstituted Pyrimidine Derivatives as Potential Antimicrobial and Anticancer Agents

Rostom

Ashour

Razik

2009

Archiv der Pharmazie

View full text Add to dashboard Cite

show abstract

“…These results demonstrate that the simple bacterial selection strategy for MTX resistance also consistently provides variants with high in vitro resistance to PMTX. Nonetheless, the chemical differences between the two antifolates and, potentially, differences in their mode of binding within the hDHFR binding site (Gangjee et al, 2006), resulted in significant differences in the trends for relative resistance to PMTX and MTX according to the location of the mutations (31/34/ 35 vs. 115) and according to the identity of the variants. Indeed, as noted above, variant F31R/Q35E offers an important change in selectivity of substrate versus antifolate, particularly with respect to PMTX.…”

Section: Discussionmentioning

confidence: 99%

“…PMTX inhibits thymidylate synthase (TS) as well as glycinamide ribonucleotide transformylase (GART) and DHFR (Chattopadhyay et al, 2007;Ferraldeschi et al, 2007;Longo-Sorbello et al, 2007) and has been recently approved for treatment of solid tumours. Despite the fact that there is no crystal structure to reveal the precise binding mode of PMTX to hDHFR, its high structural homology to both the substrate DHF and the inhibitor MTX (Figure 1) as well as modelling studies (Gangjee et al, 2006) suggest that it should also share a fraction of those binding contacts. We hypothesize that mutations resulting in MTX resistance will result in cross-resistance to PMTX.…”

Section: Introductionmentioning

confidence: 99%

Selectively weakened binding of methotrexate by human dihydrofolate reductase allows rapid ex vivo selection of mammalian cells

Volpato

Mayotte

Fossati

et al. 2011

J of Molecular Recognition

View full text Add to dashboard Cite

Ex vivo selection of transduced hematopoietic stem cells (HSC) with drug-resistance genes offers the possibility to enrich transduced cells prior to engraftment, toward increased reconstitution in transplant recipients. We evaluated the potential of highly methotrexate (MTX)-resistant variants of human dihydrofolate reductase (hDHFR) for this application. Two subsets of hDHFR variants with reduced affinity for MTX that had been previously identified in a bacterial system were considered: those with substitutions at positions 31, 34, and/or 35, and those with substitutions at position 115. The variants were characterized for their resistance to pemetrexed (PMTX), an antifolate that is related to MTX. We observed a strong correlation between decreased binding to both antifolates, although the identity of specific sequence variations modulated the correlation. We chose a subset of hDHFR variants for tests of ex vivo MTX resistance, taking into consideration their residual specific activity and their decrease in affinity for the related antifolates. Murine myeloid progenitors and other differentiated hematopoietic cells were transduced and exposed to MTX in a nucleotide-free medium. Bone marrow (BM) cells including 15% cells infected with F31R/Q35E were enriched to 98% transduced cells within 6 days of ex vivo selection. hDHFR variant F31R/Q35E allowed a strong ex vivo enrichment upon a short exposure to MTX relative to a less resistant variant of hDHFR, L22Y. We have thus demonstrated that bacterial selection of highly antifolate-resistant hDHFR variants can provide selectable markers for rapid ex vivo enrichment of hematopoietic cells.

show abstract

“…Estrutura da halofantrina absorção, mas podem ser usados no tratamento de diversas doenças, inclusive câncer. 38 Esses fármacos são divididos em dois grupos de acordo com seus mecanismos de ação. O primeiro grupo (antifolatos do tipo I) inclui compostos que são competidores do ácido para-aminobenzóico (PABA), interrompendo a formação do ácido di-hidrofólico, necessário para a síntese de ácidos nucléicos, através da inibição da di-hidropteroato sintase.…”

Section: Figura 3 Estruturas Da Pamaquina (A) E Da Primaquina (B)unclassified

Malária: aspectos históricos e quimioterapia

França¹,

Santos²,

Figueroa‐Villar³

2008

Quím. Nova

View full text Add to dashboard Cite

Dual Inhibitors of Thymidylate Synthase and Dihydrofolate Reductase as Antitumor Agents: Design, Synthesis, and Biological Evaluation of Classical and Nonclassical Pyrrolo[2,3-d]pyrimidine Antifolates

Abstract: We designed and synthesized a classical analog N- [4-[(2-amino-6-ethyl-3,4-dihydro-4-oxo-7H-pyrrolo

Cited by 44 publications

References 48 publications

Synthesis and Biological Evaluation of Some Novel Polysubstituted Pyrimidine Derivatives as Potential Antimicrobial and Anticancer Agents

Synthesis and Biological Evaluation of Some Novel Polysubstituted Pyrimidine Derivatives as Potential Antimicrobial and Anticancer Agents

Selectively weakened binding of methotrexate by human dihydrofolate reductase allows rapid ex vivo selection of mammalian cells

Malária: aspectos históricos e quimioterapia

Contact Info

Product

Resources

About