Folate-Based Inhibitors of Thymidylate Synthase:  Synthesis and Antitumor Activity of γ-Linked Sterically Hindered Dipeptide Analogues of 2-Desamino-2-methyl-N¹⁰-propargyl-5,8-dideazafolic Acid (ICI 198583)

Abstract

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.

Trimethoprim: An Old Antibacterial Drug as a Template to Search for New Targets. Synthesis, Biological Activity and Molecular Modeling Study of Novel Trimethoprim Analogs

“…The term "designed multiple ligands" was coined by Morphy Our last review presents the current state of knowledge on the modification of known DHFR inhibitors as anticancer agents, and shows that multitarget compounds represent a promising approach for discovering new structures for anticancer therapy [20]. Moreover, numerous quotations from literature show the variety of structures bearing 1,3-thiazole [21], 1,3,4-thiadiazole, or 1,2,4-triazole moiety in various fused heterocyclic systems [22][23][24], as well as 1,3,5-triazine [25][26][27][28] or biguanide and dihydrotriazine derivatives [29].…”

Substituted Quinazolines, Part 2. Synthesis and In‐Vitro Anticancer Evaluation of New 2‐Substituted Mercapto‐3H‐quinazoline Analogs

“…Interest in quinazolines as anticancer agents has further increased since the discovery of raltitrexed (1) and thymitaq (2) (Figure 1) and their activity as thymidylate enzyme inhibitors [1,2]. 4-Anilinoquinazolines represent as a new class of antitumor drugs [3,4].They were found to inhibit the epidermal growth factor receptor (EGFR) tyrosine kinase overexpression through the inhibition of EGFR autophosphorylation and EGF-stimulated signal transduction [5,6].…”

Synthesis, Anticancer Screening of Some Novel Trimethoxy Quinazolines and VEGFR2, EGFR Tyrosine Kinase Inhibitors Assay; Molecular Docking Studies

“…Quinazoline is one of the most common groups of heterocyclic compounds used in medicine because of its broad variety of biological activities. We are particularly interested in the present work with quinazoline derivatives that have been identified as a class of heterocyclic cancer chemotherapeutic agents with significant therapeutic effects [ 1 , 2 ]. For example, the effects of 2-chloro-4-anilino quinazoline derivatives as dual inhibitors for VEPGR and EGFR [ 3 ].…”