Controlled Exploration of Structural Databases: The Case of Farnesyl Transferase Inhibitors

Abstract

Among the newer and promising weapons against cancer are Farnesyl Transferase Inhibitors (FTI). Indeed it is known that the enzyme Farnesyl Transferase (FT), catalyses the prenylation of cysteine residues of several proteins associated with cancer progression, including oncogenic forms of Ras.FTI could alter tumour progression. Exploration of our corporate structural database, based on concepts of diversity and similarity, brought forward a quinazoline-2,4-dione possessing weak farnesyl transferase inhibitory properties. A systematic modulation of structural parameters allowed the elaboration of a series of analogs out of which the most potent compound (21b) exhibited an IC(50) of 19 nM on FT, an excellent cellular activity on the oncogenic H-Ras-transfected cell line Ras #1, as well as selectivity (ratio of IC(50) on parental RAT2 cells/ IC(50) on Ras#1 cells > 2000). Moreover this compound also showed encouraging "in vivo" activity. The synthesis of these new chemical entities as well as the structure activity relationships found following pharmacological testing, is described.

Discovery of Quinazoline-2,4(1H,3H)-Dione Derivatives as Potential Antibacterial Agent: Design, Synthesis, and Their Antibacterial Activity

“…Moreover, the appearance of signals assignable to the new (CONHNH 2 ) groups at 9. 30 The key intermediate 3 could provide the opportunity for further novel quinazoline-2,4(1H,3H)-dione derivatives and have been prepared based on the synthetic producers displayed in Scheme 2. The reaction of compound 3 with diethyl ethoxymethylenemalonate or ethyl ethoxymethylene cyanoacetate under the reflux condition in acetic acid affording the malonate derivative 9a or cyanoacetate derivative 9b as a mixture of E/Z isomers, respectively.…”

“…Several reports have revealed that the unique quinazoline scaffolds possess several and diverse pharmacological activities such as antimicrobial, antimalarial, anticonvulsant, anti-inflammatory, antihypertensive, cholinesterase inhibitory, anti-diabetic, and anticancer activities [1]. Among the most important quinazoline families are quinazoline-2,4(1H,3H)-dione derivatives, and the various studies have reported several analogues representing a wide variety of biological activities, for example, antimicrobial [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18], anticancer [19][20][21][22][23][24][25][26][27][28][29][30][31][32], antiplatelet [33], antihypertensive [34], antioxidant [35], anticonvulsant [36][37][38], anti-inflammatory [39], phosphodiesterase (PDE) 4 inhibition [40], 5-HT3A receptor antagonist [41], and cyclin-dependent kinase 5 (CDK5) inhibition [42].…”

A Series of 2,4(1H,3H)-Quinazolinedione Derivatives: Synthesis and Biological Evaluation as Potential Anticancer Agents

“…Various literatures report numerous 2,4(1H,3H)quinazolinedione analogues showing a wide variety of biological activities such as anticancer [7][8][9][10][11][12][13][14][15][16][17][18][19][20], antimicrobial [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37], antihypertensive [38][39][40], anticonvulsant [41][42][43][44][45][46][47][48][49], anti-inflammatory [50], 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonist [51], phosphodiesterase (PDE) 4 inhibition [52,53], calcium-independent phosphodiesterase enzyme inhibition (CaIPDE) [54], cyclin-dependent kinase 5 (CDK5) inhibition…”