Research And Applications Of Some Pyrimidine-fused Cyclic Compounds In Drug Development

With a DOS (diversity-oriented synthesis) approach,the installation of suitablefunctionalities at suitable places of certain privileged structure may lead to a higherscreening hit rate later.This strategy of building libraries of small molecules basedon some privileged structures has attracted many medicinal chemists,representingone trend in lead discovery in recent years.1)Many bio-active compounds contain pyrimidine-fused cyclic structures,which also occur in many drugs on market or under clinical stage.During oursynthesis of 6-ethyl-7-fluoro-4-hydroxy uracil,the key intermediate of Voriconazole,we found Pd-C/H₂/NaHCO₃ system can replace the chlorine atom in the pyrimidinering with a hydrogen atom efficiently.Further application study showed that many2-chloropyrimidines can be obtained regioselectively from readily available2,4-dichloropyrimidines using above system in good to excellent yields,constitutingan useful alternative synthesis of 2-chloropyrimidines.Based on above synthetic methodology study,we designed and prepared threepyrimidine building blocks A1-3 with 2-3 different reacting points.Employingsubstitution and Suzuki coupling reaction,aryl amine blocks B1-5,secondary amineblocks C1-6 and boric acid blocks D1-10 were installed to block A1 smoothly,leading to the construction of Library 1 containing 80 compounds.Library 1 wasevaluated on protein kinase c-Met and Adenosine Receptors.LXY-78,the mostpotent compound on c-Met in Library 1,displayed a 47.8% enzyme inhibition inconcentration of 10 mg/mL.Evaluations on Adenosine Receptors are currently underprogress.2)Within recent years,4-(6-Amino-purin-9-yl)-2(S)-hydroxy-butyric acidmethyl ester (DZ2002) has been recognized as a potent typeâ…¢reversible inhibitor ofSAHH.DZ2002 is able to reversibly bind to the open form of the enzyme, maintaining a similar potency with much reduced toxicity which hampers furtherclinical applications of irreversible SAHH inhibitors.Biological study indicatesDZ2002 is a promising noval therapeutic agent for immune-related diseases.Due to its promising prospect,there is a need to develop a practical syntheticprocess to meet the sample need for related pre-clinical study.Our synthesis startedwith cheap and commercially available optical malic acid.In brief,(S)-malic acid wasfirst transformed to acetonide.Acetonide was reduced to alcohol,which wasimmediately converted to its tosylate.Coupling of tosylate with adenine gave desiredkey intermediate in a yield of 32% after silica-gel chromatograph.The keyintermediate was readily transformed to DZ2002 upon spontaneous deprotection andesterification in methanol solution of HCl.Because of the rigid conformation ofacetonide during reaction sequences,2-chiral center was highly reserved and potentialracemization was avoided.Following this process,target DZ202 was obtained in atotal yield of 6.54% after 5 steps reaction and recrystallization.According to thisprocess,about 120 grams of DZ2002 was synthesized and used for related biologicalstudy.We also designed and synthesized DZ2002 related steroisomers so as toinvestigate the necessaty of chiral center.Later biological study showed that that(S)-DZ2002 was the strongest inhibitor among four compounds (IC₅₀=21.2μM).The order of enzyme inhibition potency was (S)-Z2002＞(Rac)-DZ2002＞(R)-DZ2002＞(Ketone)-DZ2002.Respective suppressive potency appeared to matchthe inhibitory potency of the SAHH.These results indicated that maintenance of2-chiral center in the molecule as (S)-configuration is important for binding withSAHH.Simplified docking results showed that different numbers of hydrogen bondsinteracted with SAHH was formed providing useful information to understand theirefficacy difference.