Synthesis and Antitumor Activities of Novel 6-5 Fused Ring Heterocycle Antifolates: N-[4-[.omega.-(2-Amino-4-substituted-6,7-dihydrocyclopenta[d]pyrimidin-5-yl)alkyl]benzoyl]-L-glutamic Acids

Kotake, Yoshihiko; Iijima, Atsumi; Yoshimatsu, Kentaro; Tamai, Naoko; Ozawa, Yoichi; Koyanagi, Nozomu; Kitoh, Kyosuke; Nomura, Hiroaki

doi:10.1021/jm00037a012

Cited by 19 publications

(21 citation statements)

References 2 publications

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“…Miwa et al8•9 Taylor et al,10 and Shih and Gosset11 have reported the synthesis of classical 2,4-diamino-, 2-amino-4-oxo-, and 2-amino-5-substituted pyrrolo[2,3-d]pyrimidines as inhibitors of DHFR and TS and as effective antitumor agents. A classical 2,4-diamino-5-substituted-pyrazolo- [3,4-d]pyrimidine antifolate was also shown to possess significant cytotoxicity.12 Kotake et al 13 have reported the synthesis of classical 2,4-diamino-5-substitutedcyclopenta[d]pyrimidines as potent inhibitors of DHFR and as effective antitumor agents. In addition we14 recently reported the synthesis of novel, classical 2,4diamino-5-substituted-furo [2,3-d]pyrimidines 1 and 2 as potential antifolates and antitumor agents which could bind, in either the antifolate (MTX) orientation or the substrate (folate) orientation, to DHFR.…”

mentioning

confidence: 99%

Effect of bridge region variation on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines

Gangjee¹,

Devraj²,

McGuire³

et al. 1995

J. Med. Chem.

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Variation of the bridge linking the heterocyclic ring and p-aminobenzoyl-L-glutamate portions of our previously described classical 2,4-diaminofuro[2,3-d]pyrimidines 1 and 2 are reported as inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and as antitumor agents. Specifically -CH2CH2- and -CH2NHCH2- bridged analogues, N-[4-[2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl) ethyl]benzoyl]-L-glutamic acid (3) and N-[4-[[N-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl) methyl]amino]methyl]benzoyl]-L-glutamic acid (4), respectively, were synthesized. Compound 3 was obtained via a Wittig reaction of the tributylphosphonium salt of 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine (5) and methyl 4-formylbenzoate (6) followed by reduction and coupling with the diethyl ester of L-glutamic acid. Compound 4 was synthesized by the nucleophilic displacement of 5 with diethyl N-[4-(aminomethyl)benzoyl]-L-glutamate (15) and saponification. Both analogues were evaluated in vitro as inhibitors of DHFRs from (recombinant) human, human CCRF-CEM cells, and Lactobacillus casei. Compound 3 showed moderate activity (IC50 10(-6)-10(-7) M). Compound 4 was essentially inactive (IC50 10(-5) M, CCRF-CEM). The compounds were also evaluated against TS from (recombinant) human and L. casei and were of low activity (IC50 10(-5) M). The three-atom-bridged analogue 4 was somewhat more inhibitory to human TS than methotrexate (MTX). Compound 3 inhibited the growth of tumor cells in culture (IC50 10(-7) M) while 4 showed a low level of growth inhibitory activity. The inhibition of the growth of leukemia CCRF-CEM cells by both compounds parallels their inhibition of CCRF-CEM DHFR. Analogue 3 was a good substrate for human folylpolyglutamate synthetase (FPGS) derived from CCRF-CEM cells (Km 8.5 microM). Further evaluation of the growth inhibitory activity of 3 against the MTX-resistant subline of CCRF-CEM cells (R30dm) with decreased FPGS indicated that poly-gamma-glutamylation was important for its action. Protection studies with 3 in the FaDu squamous cell carcinoma cell line indicated that inhibition was completely reversed by leucovorin [(6R,S-5-formyltetrahydrofolate] or by a combination of thymidine and hypoxanthine, suggesting an antifolate effect directed at DHFR.

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confidence: 99%

Effect of bridge region variation on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines

Gangjee¹,

Devraj²,

McGuire³

et al. 1995

J. Med. Chem.

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“…According to general procedure A, 4k was prepared from tert-butyl 4-(2-hydroxyethyl)benzoate (prepared according to a literature procedure; 29 676 mg, 3.04 mmol), iodine (848 mg, 3.34 mmol), PPh 3 (787 mg, 3.34 mmol), and imidazole (249 mg, 3.65 mmol). The crude product was purified by Yamazen YFLC AI-580 using Universal Column SiOH (hexane/EtOAc) to provide 4k.…”

Section: Tert-butyl 4-(2-iodoethyl)benzoate (4k)mentioning

confidence: 99%

Allyl 4-Chlorophenyl Sulfone as a Versatile 1,1-Synthon for Sequential α-Alkylation/Cobalt-Catalyzed Allylic Substitution

Sekino

Sato

Kuwabara³

et al. 2020

Synthesis

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Despite their unique potential as rare 1,1-dipole synthons, allyl sulfones are rarely used in target-oriented syntheses, likely due to the lack of a general catalytic method for their branch-selective allylic substitution. Herein, we identified allyl 4-chlorophenyl sulfone as a versatile linchpin for both base-mediated α-derivatization and subsequent cobalt-catalyzed allylic substitution. The sequential transformations allow for highly regioselective access to branched allylic substitution products with a variety of aliphatic side chains. The photoredox-enabled cobalt catalysis is indispensable for achieving high yields and regioselectivity for the desulfonylative substitution in contrast to traditional metal-catalyzed protocols, which lead to inferior outcomes in the corresponding transformations.

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“…Compounds 3 a,c selectively led to the unsaturated a-cyano ketones 11 a,c in high yields, without erosion of the enantioselectivity (Scheme 2a). Cyclic b-oxoalkenenitriles are useful electrophilic intermediates [25] and polycyclic b-oxoalkenenitriles showed to be potent inhibitors of the enzyme 5a-reductase. [26] In contrast, diastereoisomers 3 a',c', treated under the same conditions, underwent tautomerization to compounds 12 a,c maintaining the level of enantioselectivity (Scheme 2b).…”

Section: Abstract: Asymmetric Synthesis; Organocatalysis; Spirocyclicmentioning

confidence: 99%

Asymmetric Synthesis of Pyrazolone Fused Spirocyclohexeneimines via a Vinylogous Michael/Cyclization Cascade Reaction

2018

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Diastereoisomeric pyrazolone-fused spirocyclohexenimines, bearing contiguous all-carbon quaternary and tertiary stereocenters, are readily synthesized for the first time in good to excellent yield (up to 98%) and high enantioselectivity (up to 97% ee) via vinylogous Michael reaction/cyclization cascade reaction of a-arylidene pyrazolones and a,a-dicyanoalkylidenes. The formal [4 + 2] atom-economical annulation proceeds with commercially available Takemoto's catalyst under mild reaction conditions. Scale-up reaction and posttransformation of the products were also demonstrated.The interest of chemists toward the asymmetric synthesis of spirocyclic compounds constantly increased in the last decade. [1] This is a highly challenging goal in organic synthesis as the quaternary stereocenter links two cyclic compounds, often decorated with additional tertiary or quaternary stereocenters, whose stereochemistry has to be controlled. Most of these studies were inspired by natural and synthetic bioactive compounds, bearing heterocyclic and carbocyclic units, with the idea to create new hybrid spirocylic compounds of potentially widespread biological activities. Among the classes of spirocyclic compounds, those bearing the pyrazolone unit and the carbocyclic cyclohexane, [2] cyclohexanone, [3] cyclohexenone [4] and cyclohexadiene rings, [5] have attracted considerable interest due to their relevance in medicinal chemistry ( Figure 1). [6] Some selected examples, illustrated in Figure 1, showed that these compounds display diverse and valuable biological activities as phosphodiesterase inhibitor, [2b] antimicrobial, [3a] anticancer [4] and antiinflammatory agents. [7] From a synthetic point of view, the methodologies designed to prepare these compounds essentially relied on organocatalytic cascade double Michael reaction or double Michael reaction followed by aldol reaction. [8] These practical approaches successfully guaranteed mild and environment friendly conditions as well as high control of the stereoselectivity. In this context, a-alkylidene pyrazolinones have been used as Michael acceptors to obtain a few complex spirocyclic cyclohexane derivatives, bearing quaternary and tertiary stereocenters, as demonstrated by the groups of Rios, [9] Wang [3c,10] and Enders [11] (Scheme 1). The organocatalytic approaches were successfully developed using popular Hayashi-Jørgensen's catalyst and Cinchona alkaloids derived primary or tertiary amines. Very recently, Biju [12] and Li [13] applied a less inves-Figure 1. Representative examples of bioactive spiropyrazolones containing six-membered rings.

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Synthesis and Antitumor Activities of Novel 6-5 Fused Ring Heterocycle Antifolates: N-[4-[.omega.-(2-Amino-4-substituted-6,7-dihydrocyclopenta[d]pyrimidin-5-yl)alkyl]benzoyl]-L-glutamic Acids

Cited by 19 publications

References 2 publications

Effect of bridge region variation on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines

Effect of bridge region variation on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines

Allyl 4-Chlorophenyl Sulfone as a Versatile 1,1-Synthon for Sequential α-Alkylation/Cobalt-Catalyzed Allylic Substitution

Asymmetric Synthesis of Pyrazolone Fused Spirocyclohexeneimines via a Vinylogous Michael/Cyclization Cascade Reaction

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