ABSTRACT
Cyclopenta[g]quinazoline-based inhibitors of thymidylate synthase (TS) possess a chiral centre at the 6-position of the molecule. The effect of this chirality on the inhibition of TS was investigated by synthesising compounds 6S-1a-c, 6R-1a-c. It was shown, in particular with the diastereoisomers 6S-1c, 6R-1c, that the inhibitory activity against TS is mainly due to the 6S diastereoisomer rather than the 6R diastereoisomer, which is virtually inactive.
Subject(s)
Folic Acid Antagonists/chemistry , Folic Acid Antagonists/pharmacology , Thymidylate Synthase/antagonists & inhibitors , Biochemistry/methods , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Drug Evaluation, Preclinical , Quinazolines/chemistry , Quinazolines/pharmacology , Structure-Activity RelationshipABSTRACT
Derivatives of 2'-deoxyuridine in which the 5'-OH group is replaced by a 2,3,6-trifluoro-5-hydroxy-4-nitrophenoxy or a 4-carboxy-2,3,6-trifluoro-5-hydroxyphenoxy group have been prepared for evaluation as possible dUTP analogues. They showed a weak ability to displace radiolabelled dUTP from a dUTP-binding antiserum. The corresponding compounds lacking the three fluorine substituents were prepared for comparison.
Subject(s)
Deoxyuracil Nucleotides/chemistry , Deoxyuridine/analogs & derivatives , Deoxyuridine/chemical synthesis , Cross Reactions , Deoxyuracil Nucleotides/chemical synthesis , Humans , Magnetic Resonance Spectroscopy , Pyrophosphatases/metabolism , Radioimmunoassay , Spectrometry, Mass, Electrospray Ionization , Tumor Cells, CulturedABSTRACT
Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.
Subject(s)
Antineoplastic Agents/chemical synthesis , Drug Design , Enzyme Inhibitors/chemical synthesis , Folic Acid Antagonists/chemical synthesis , Glutamates/chemical synthesis , Quinazolines/chemical synthesis , Thymidylate Synthase/antagonists & inhibitors , Animals , Antineoplastic Agents/therapeutic use , Cell Division/drug effects , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Folic Acid Antagonists/pharmacology , Folic Acid Antagonists/therapeutic use , Glutamates/pharmacology , Glutamates/therapeutic use , Leukemia L1210/drug therapy , Leukemia L1210/enzymology , Leukemia L1210/pathology , Methotrexate/metabolism , Mice , Molecular Structure , Quinazolines/pharmacology , Quinazolines/therapeutic use , Structure-Activity Relationship , Tritium , Tumor Cells, CulturedABSTRACT
A novel diphosphate mimic, the 2,3,6-trifluoro-5-hydroxy-4-nitrophenoxy group (1), has been employed as the template in the solid-phase synthesis of novel farnesyl transferase inhibitors using the Mitsunobu reaction. The most potent inhibitor (farnesyloxy-5-hydroxy-2,3,6-trifluoro-4-nitrobenzene) displayed an IC50 of 6.3 microM versus farnesyl transferase.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , FarnesyltranstransferaseABSTRACT
In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or propargyl group was incorporated into the gamma-glutamyl amide bond of gamma-linked L,L dipeptide derivatives of ICI 198583, such as ICI 198583-gamma-L-Glu. In addition, steric bulk was introduced on either side of the gamma-glutamyl bond of ICI 198583-gamma-L-Glu or ICI 198583-gamma-L-Ala. The resulting dipeptide analogues, e.g., ICI 198583-gamma-MeGlu and ICI 198583-gamma-Aib, were apparently stable to in vivo hydrolysis but poorer inhibitors of TS and L1210 cell growth. However, introduction of 7-Me, 2'-F substitution into the quinazoline nucleus gave significant improvement in the inhibitory activity against thymidylate synthase. Compounds 28-30, the 7-Me, 2'-F derivatives of ICI 198583-gamma-MeGlu, ICI 198583-gamma-EtGlu, and ICI 198583-gamma-PgGlu, respectively, were potent inhibitors of TS (K(iapp) = 0.21-1.1 nM) and L1210 cell growth (IC50 = 0.05-0.34 microM) and were similar to that seen with the most potent gamma-linked L,D dipeptide derivatives of ICI 198583 previously synthesized. Furthermore, the low cross-resistance ratios for the L1210:R(D1694)/L1210 cell line indicated that 28-30 do not undergo polyglutamation.