A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus

Abstract

Thymidylate synthase (TS; EC 2.1.1.45) is a critical enzyme in the de novo synthesis of thymidylate (dTTP) and has long been recognized as a target for chemotherapeutic intervention. Of interest has been a class of quinazoline-based compounds that fall into three general biochemical sub-type of antifolate TS inhibitor; those which:1. are transported into the cell via the reduced folate carrier (RFC) and are subsequently polyglutamated by folylpolyglutamate synthetase (FPGS; EC 6.3.2.17), e.g. Tomudex TM (raltitrexed; ZD1694; reviewed in Jackman et al, 1996a) 2. use the RFC but which do not undergo intracellular polyglutamation, e.g ZD9331 (Jackman et al 1995c, 1997a) 3. do not interact with the RFC or FPGS, which may either retain the 'classical' (glutamate-containing) structure of antifolates Jackman et al, 1997b;Melin et al, 1997) or be 'non-classical' lipophilic derivatives (Skelton et al, 1994a(Skelton et al, , 1994b).This latter sub-type was originally developed with the aim of achieving good TS inhibition whilst circumventing resistance due to defective RFC and/or polyglutamation mechanisms in tumours. Based on the structure of ZM198583 (2-desamino-2-methyl-N 10 -propargyl-5,8-dideazafolic acid; Jackman et al, 1991), these compounds have an aminomethyl 2-, 3-or 4-pyridine in place of the glutamate residue (Skelton et al, 1997). Their highly lipophilic nature [LogP (partition coefficient) ~ 3.5] suggests that they are likely to enter the cell by passive diffusion, and the absence of the glutamate ligand precludes intracellular polyglutamation.The pyridine derivatives were generally good inhibitors of isolated mammalian TS (IC 50~ 0.1-2 µM). However, although compounds with the 2-or 4-pyridine structure targeted TS (at least partially) in W1L2 human lymphoblastoid cells, those with the 3-pyridine configuration did not, since they were active in the presence of exogenous salvageable thymidine (dThd; Jackman et al, 1996b; Skelton et al, 1997). They were also active against cell lines resistant to antifolates due to elevated TS or dihydrofolate reductase (DHFR) enzyme levels (Skelton et al, 1997). Furthermore, there were analogues in the 3-pyridine series which were extremely potent inhibitors of in vitro tumour cell growth (IC 50~ 1 nM). For example, substitution with Cl or Br at the C7 position of the quinazoline ring was found to improve growth inhibitory potency against L1210 and W1L2 cell lines bỹ 100-fold (Skelton et al, 1997). A detailed account of structure-activity relationships will be given elsewhere (Skelton et al, manuscript in preparation). Thus, based on its good growth inhibitory potency (W1L2 72 h IC 50 = 0.0028 µM) and apparently folate-independent mechanism, the 7-bromo-3-pyridine derivative CB30865 (ZM242421, p-[N-(7-bromo-3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide; Figure 1) was selected for further in vitro studies.A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus LA ...

Comparative expressed sequence hybridization to chromosomes for tumor classification and identification of genomic regions of differential gene expression

“…The cell line W1L2:R865 is resistant to a lipophilic quinazoline-based aminomethyl pyridine compound, CB30865, and is associated with amplification at 7q22, as determined by CGH (8). Hybridization of cDNA to chromosomes generally results in signals that are difficult to detect because of the small target footprint of coding sequence in the genome.…”

“…The cell line W1L2:R865 is resistant to the compound CB30865 and derived from the leukemic WIL2 cell line (8). Four rhabdomyosarcoma (RMS) cell lines were used in the study: SCMC-RM2 (9), RH30 (10), RMS (11), and RD (from the American Type Tissue Culture Collection).…”

PBEF/NAMPT/Visfatin: A Promising Drug Target For Treating Rheumatoid Arthritis?

“…Although possessing potent anti-tumorigenic activity, CB-30865 did not act via inhibition of thymidylate synthase or other known folatedependent pathways; suggesting a novel locus of action for this compound [112]. A subsequent study looking at three quinazoline-based analogs confirmed that the 3-pyridine structure of CB30865 conferred more potent inhibitory effects than structurally similar 2-pyridine and 4-pyridine compounds [113].…”

“…| Review www.future-science.com 7q22 [113], which is the location of the NAMPT gene [18]. However, the link between NAMPT and CB30865 was not determined until 2010; using small-molecule affinity purification, a single prominent protein of about 55 kDa was identified in complex with MPI-0479883, a 3-pyridyl analog of CB30865.…”

Nicotinamide Phosphoribosyltransferase Inhibitors, Design, Preparation, and Structure–Activity Relationship

“…NAMPT inhibitors. 1, APO866 (activity see Table1); 2, CHS-828 (activity see Table 1); 3, EB 1627 (pro-drug of CHS828); TRON-8 (IC 50 (SH-SY5Y) 3.8 nM)) 23 ; and CB30865 (IC 50 (W1L2) 2.8 nM) 37 .…”