The effect of side-chain, para-aminobenzoyl region, and B-ring modifications on dihydrofolate reductase binding, influx via the reduced folate carrier, and cytotoxicity of the potent nonpolyglutamatable antifolate Nα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine

Rosowsky, A.; Wright, Joel E.; Vaidya, Chitra M.; Forsch, Ronald A.

doi:10.1016/s0163-7258(99)00055-8

Cited by 28 publications

(35 citation statements)

References 64 publications

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“…3). Aminopterin and MTX are excellent inhibitors of DHFR; the potent cytotoxic activity of MTX is a reflection of its extremely tight binding and consequent inhibition of the target enzyme DHFR (Ki=5 pM) [12][13][14]. Likewise, potent inhibition of other folate-dependent enzymes including TS and AICARTF by certain congeners of MTX also leads to the disruption of purine and pyrimidine nucleotide biosynthesis, thereby resulting in cessation of DNA synthesis and cell death.…”

Section: Antifolates and Their Mode Of Actionmentioning

confidence: 99%

“…One of the best studied mechanisms of antifolate cytotoxicity is that of MTX and other 4-amino-folate inhibitors of DHFR. Thus, whereas MTX potently inhibits DHFR with a Ki at the pM range [12][13][14], a free intracellular MTX level of at least 1 μM is required in order to attain a complete suppression of DHFR activity and cessation of THF formation in living cells as also corroborated by computer simulations [15][16][17][18]. Thus, nearly six orders of magnitude higher MTX concentrations than its Ki for DHFR are required to completely block the catalytic activity of this enzyme.…”

Section: Antifolates and Their Mode Of Actionmentioning

confidence: 99%

“…Over the recent decades, second and third generation antifolates were rationally synthesized (Fig. 3); these include more potent inhibitors of DHFR such as PT523 and some of its derivatives which inhibit DHFR with a 15-fold greater affinity than MTX (Ki = 0.35 pM) [14]. Furthermore, DHFR inhibitors like edatrexate (10-ethyl- 10-deaza-aminopterin) and pralatrexate (10-propargyl-10-deazaaminopterin; PDX) have been rationally synthesized which display unique properties such as much better transport and increased polyglutamylation leading to augmented cellular accumulation and retention [24,25].…”

Section: Antifolates and Their Mode Of Actionmentioning

confidence: 99%

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Molecular basis of antifolate resistance

Assaraf

2007

Cancer Metastasis Rev

303

281

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Folates play a key role in one-carbon metabolism essential for the biosynthesis of purines, thymidylate and hence DNA replication. The antifolate methotrexate has been rationally-designed nearly 60 years ago to potently block the folate-dependent enzyme dihydrofolate reductase (DHFR) thereby achieving temporary remissions in childhood acute leukemia. Recently, the novel antifolates raltitrexed and pemetrexed that target thymidylate synthase (TS) and glycineamide ribonucleotide transformylase (GARTF) were introduced for the treatment of colorectal cancer and malignant pleural mesothelioma. (Anti)folates are divalent anions which predominantly use the reduced folate carrier (RFC) for their cellular uptake. (Anti)folates are retained intracellularly via polyglutamylation catalyzed by folylpoly-gamma-glutamate synthetase (FPGS). As the intracellular concentration of antifolates is critical for their pharmacologic activity, polyglutamylation is a key determinant of antifolate cytotoxicity. However, anticancer drug resistance phenomena pose major obstacles towards curative cancer chemotherapy. Pre-clinical and clinical studies have identified a plethora of mechanisms of antifolate-resistance; these are frequently associated with qualitative and/or quantitative alterations in influx and/or efflux transporters of (anti)folates as well as in folate-dependent enzymes. These include inactivating mutations and/or down-regulation of the RFC and various alterations in the target enzymes DHFR, TS and FPGS. Furthermore, it has been recently shown that members of the ATP-binding cassette (ABC) superfamily including multidrug resistance proteins (MRP/ABCC) and breast cancer resistance protein (BCRP/ABCG2) are low affinity, high capacity ATP-driven (anti)folate efflux transporters. This transport activity is in addition to their established facility to extrude multiple cytotoxic agents. Hence, by actively extruding antifolates, overexpressed MRPs and/or BCRP confer antifolate resistance. Moreover, down-regulation of MRPs and/or BCRP results in decreased folate efflux thereby leading to expansion of the intracellular folate pool and antifolate resistance. This chapter reviews and discusses the panoply of molecular modalities of antifolate-resistance in pre-clinical tumor cell systems in vitro and in vivo as well as in cancer patients. Currently emerging novel strategies for the overcoming of antifolate-resistance are presented. Finally, experimental evidence is provided that the identification and characterization of the molecular mechanisms of antifolate-resistance may prove instrumental in the future development of rationally-based novel antifolates and strategies that could conceivably overcome drug-resistance phenomena.

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Section: Antifolates and Their Mode Of Actionmentioning

confidence: 99%

Section: Antifolates and Their Mode Of Actionmentioning

confidence: 99%

Section: Antifolates and Their Mode Of Actionmentioning

confidence: 99%

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Molecular basis of antifolate resistance

Assaraf

2007

Cancer Metastasis Rev

303

281

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“…5). The respective compounds were taken from the literature [28][29][30][31][32][33][34]. The pharmacophore has been defined as above.…”

Section: Resultsmentioning

confidence: 99%

Ultrafast de novo docking combining pharmacophores and combinatorics

Gastreich¹,

Lilienthal²,

Briem³

et al. 2007

J Comput Aided Mol Des

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We report on a successful de novo design approach which relies on the combination of multi-million compound combinatorial docking under receptor-based pharmacophore constraints. Inspired by a rationale by A.R. Leach et al., we document on the unification of two steps into one for ligand assembly. In the original work, fragments known to bind in protein active sites were connected forming novel ligand compounds by means of generic skeleton linkers and following a combinatorial approach. In our approach, the knowledge of fragments binding to the protein has been expressed in terms of a receptor-based pharmacophore definition. The combinatorial linking step is performed in situ during docking, starting from combinatorial libraries. Three sample scenarios growing in size and complexity (combinatorial libraries of 1 million, 1.3 million, and 22.4 million compounds) have been created to illustrate the method. Docking could be accomplished between minutes and several hours depending on the outset; the results were throughout promising. Technically, a module compatibility between FlexX(C) and FlexX-Pharm has been established. The background is explained, and the crucial points from an information scientist's perspective are highlighted.

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“…[1] They have attracted significant attention because of their diverse biological properties such as antiplasmodial, [2] antimicrobial, [3] antihypertensive, [4] antiinflammatory, [5] anti-diabetic, [6] anticonvulsant, [7] cholinesterase inhibition, [8] anticancer, [9] dihydrofolate reductase inhibition, [10] and kinase inhibitory activities. [1] They have attracted significant attention because of their diverse biological properties such as antiplasmodial, [2] antimicrobial, [3] antihypertensive, [4] antiinflammatory, [5] anti-diabetic, [6] anticonvulsant, [7] cholinesterase inhibition, [8] anticancer, [9] dihydrofolate reductase inhibition, [10] and kinase inhibitory activities.…”

Section: Introductionmentioning

confidence: 99%

Direct Construction of Diverse Polyheterocycles Bearing Pyrrolidinediones via Rh(III)‐Catalyzed Cascade C−H Activation/Spirocyclization

et al. 2019

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Rh(III)-catalyzed cascade oxidative annulation of 2-arylquinazolinones with various maleimides to afford spiroisoindoloquinazolinones bearing pyrrolidinediones is described. Sequential ortho CÀ H functionalization and spirocyclization via aza-Michael addition result in the formation of both CÀ C and CÀ N bonds in a single operation. This atom-and step-economic strategy provides an efficient and novel approach for the syntheses of diverse polyheterocycles bearing pyrrolidinediones, starting from 2-heteroarylquinazolinones and 5-arylpyrazolopyrimidinones, in good to excellent yields.

show abstract

The effect of side-chain, para-aminobenzoyl region, and B-ring modifications on dihydrofolate reductase binding, influx via the reduced folate carrier, and cytotoxicity of the potent nonpolyglutamatable antifolate Nα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine

Cited by 28 publications

References 64 publications

Molecular basis of antifolate resistance

Molecular basis of antifolate resistance

Ultrafast de novo docking combining pharmacophores and combinatorics

Direct Construction of Diverse Polyheterocycles Bearing Pyrrolidinediones via Rh(III)‐Catalyzed Cascade C−H Activation/Spirocyclization

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