Substituted-2-Desamino-2-Methyl-Quinazolinones. A Series of Novel Antitumour Agents

Boyle, F. T.; Matusiak, Zbigniew S.; Hughes, Laura E.; Slater, Anthony M.; Stephens, T C; Smith, Marie-Louise; Brown, M.; Kimbell, Rosemary; Jackman, Ann L.

doi:10.1007/978-1-4615-2960-6_119

Cited by 11 publications

(15 citation statements)

References 3 publications

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“…Thymidine protection studies on representative examples confirmed that TS is the predominant cytotoxic locus for these series of compounds. 33 Molecular modeling s t~d i e s~~2~~ based on the crystal structure^^^,^^ of ternary complexes of CB 3717, a pyrimidine nucleotide and E. coli TS indicated that a 7-methyl substituent would reinforce the partially folded conformation with the p-aminobenzoate (PABA) ring inclined at an angle of 65" to the quinazolinone, which is optimum for binding to the enzyme. Our earlier s t u d i e~~,~ had also shown that a 2'-fluoro substituent gives a 2-3-fold enhancement of TS inhibition and cytotoxicity in the PABA-glutamate series, presumably through the stabilization of the almost planar conformation in this region of the molecule due to a hydrogen bond between the fluorine atom and the amidic NH of the glutamate (revealed by NMR studies).…”

Section: Resultsmentioning

confidence: 99%

Quinazoline Antifolate Thymidylate Synthase Inhibitors: Replacement of Glutamic Acid in the C2-Methyl Series

Pr¹,

Al²,

Barker³

et al. 1995

J. Med. Chem.

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The synthesis of a series of analogues of the potent thymidylate synthase (TS) inhibitor N-[4-[N-[(3,4-dihydro-2-methyl-4-oxo-6- quinazolinyl)methyl]-N-prop-2-ynylamino]benzoyl]-L-glutamic acid (ICI 198583, 1) is described in which the glutamic acid residue has been replaced by other alpha-amino acids. Most of these analogues were prepared by coupling of tert-butyl-4-(prop-2-ynylamino)benzoate (37) with 6-(bromomethyl)-3,4-dihydro-2-methyl-4-oxoquinazoline (34) followed by deprotection of the tert-butyl ester to the acid and azide-mediated coupling to the appropriate amino acid or amino acid ester. In cases where the amino acid ester was unreactive with the acid azide, a modification was used in which the quinazolinone moiety was protected as its 3-(pivaloyloxy)methyl derivative. This permitted the generation of the more reactive acid chloride of the p-aminobenzoate unit. In general these modifications result in compounds that have equivalent potency to 1 as inhibitors of isolated TS except where the amino acid lacks a lipophilic alpha-substituent. These compounds appear to require the reduced folate carrier (RFC) for transport into cells, but since they are not converted intracellularly into polyglutamated forms, they have a lower level of cytotoxicity compared to 1. The removal of the alpha-carboxylic acid has given a second set of analogues of 1 which contain simple alkyl amide, benzyl, substituted benzyl, and heterocyclic benzyl amide derivatives. These are considerably less potent than 1 as TS inhibitors but display 1-10 microM cytotoxicities due to the fact that they do not require RFC transport and can presumably readily enter cells by passive diffusion through the cell membrane. Molecular modeling and NMR studies indicated that the incorporation of, respectively, 7-methyl and 2'-fluoro substituents would favor the optimum conformation of these molecules for interaction with the TS enzyme. Accordingly, these substituents were incorporated into selected examples to give the series of analogues 47-55. These all show enhanced (approximately 10-fold) inhibition of TS compared to their unsubstituted counterparts. In the substituted benzylamides (51, 52) and heterocyclic benzyl amides (53-55) the ability to enter cells by passive diffusion results in highly potent (< 1 microM) cytotoxic agents.

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Section: Resultsmentioning

confidence: 99%

Quinazoline Antifolate Thymidylate Synthase Inhibitors: Replacement of Glutamic Acid in the C2-Methyl Series

Pr¹,

Al²,

Barker³

et al. 1995

J. Med. Chem.

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“…Lower cross-resistance was seen to the lipophilic analogue, 10, which possibly relates to a second locus of action becoming important to growth inhibition at the higher compound concentration. No cross-resistance was (Jackman et al, 1991acA 1993aMarsham et al, 1991;Boyle et al, 1993;Duch et al, 1993;Pavlovic et al, 1993;Webber et al, 1993 (Table VI). The 2.4 cross-resistance to AG337 may relate to its poor activity against the parental line (9.3 tIM) with the possibility of another locus becoming significant at the higher concentration used against the resistant cells.…”

Section: Cross-resistance Studiesmentioning

confidence: 99%

Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines

Kèlland²,

Kimbell³

et al. 1995

Br J Cancer

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“…The precipitate obtained was filtered and washed with the mixture of ether and water and dried. The product obtained was recrystallized from 95% ethanol [4][5][6][7][8].…”

Section: Synthesis Of 1-(4-oxo-2-arylquinazolin-3(4h)-yl) Aryl Semicarbazones From 1-(4-oxo-2-arylquinazolin-3(4h)yl)mentioning

confidence: 99%

“…The human cervical cancer cell line (HeLa), NIH 3T3 mouse embryonic fibroblasts were obtained from National Center for cell science (NCCS), Pune. The HeLa cells were grown in Eagles Minimum Essential Medium containing 10% fetal bovine serum (FBS) and NIH 3T3 fibroblasts were grown in Dulbeccos Modified Eagles Medium(DMEM) containing 10%FBS [8][9][10]. For the screening experiment, the cells were seeded into 96-well plates in 100µl of respective medium containing 10% FBS , at a plating density of 10,000 cells/well and incubated at 37 °C, 5%CO 2 , 95% air and 100% relative humidity for 24hrs prior to addition of samples.…”

Section: In-vitro Anticancer Screeningmentioning

confidence: 99%

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"Synthesis of Some Novel Quinazoline Derivatives Having Anti-Cancer Activity"

Arunachalam¹

2017

GJPPS

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General proceduresSynthesis of 2-aryl-3-amino-4(3H) quinazolinone from anthranilic acid: Anthranilic acid (0.1mol, 13.71gm) was dissolved in 30ml of dry pyridine by stirring slowly at room temperature. The solution was cooled to 0 °C and a solution of an aromatic acid chloride (4-Chlorobenzoyl chloride) (0.02mole) in 30ml of dry pyridine was added slowly with constant stirring [4,5]. After this addition the reaction mixture was further stirred for half an hour at room temperature and set aside for 1h.

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Substituted-2-Desamino-2-Methyl-Quinazolinones. A Series of Novel Antitumour Agents

Cited by 11 publications

References 3 publications

Quinazoline Antifolate Thymidylate Synthase Inhibitors: Replacement of Glutamic Acid in the C2-Methyl Series

Quinazoline Antifolate Thymidylate Synthase Inhibitors: Replacement of Glutamic Acid in the C2-Methyl Series

Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines

"Synthesis of Some Novel Quinazoline Derivatives Having Anti-Cancer Activity"

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