One-pot Synthesis Of 4-aminoquinazolines And Its Application In Preparation Of P-3A Analogs

In this dissertation, a useful method was developed to prepare the 4-aminoquinazoline heterocyclic nucleus, which entails a two-step one-pot procedure leading to 4-aminoquinazolines up to good yields. The application of this method to synthesis of 4-aminoquinazoline bleomycin analogs is envisioned. And a P-3A thiazole analog was designed and synthesized.In Chapter One, biological activity and synthesis of 4-aminequinazoline were reviewed. A new one-pot two-step procedure was developed to prepare 4-aminoquinazolines from carboxylic acids and 2-aminobenzonitriles. Various carboxylic acids, including aromatic, aliphatic, and amino acids, are suitable substrates for this new method.Quinazolines are a family of compounds with a variety of pharmacological properties, such as analgesic, narcotic, anti-malarial, sedative and hypoglycaemic ones. 4-Aminoquinazolines are useful as fungicides and as anti-inflammatory, anti-cancer, anti-microbial and anti-hypertensive agents. 4-Aminequinazolines have not been the object of new synthetic developments in the last few years and recent reports on their preparation use only classical methods via 4-chloroquinazolines, an important synthetic intermediate as they can be derivatised further through nucleophilic attack at the C-4 position. 4-Aminoquinazolines were prepared from 2-aminobenzonitrile with either a nitrile or an orthoester under microwave conditions. Recently, 2-aminonitrile was cyclized with formic acid at the elevated temperature of 200℃leading to 5,6-dihydro-quinazolines; 2-aminobenzamide was cyclized with anilines and orthoesters to give 4-arylaminoquinazolines. But the cyclization with 2-aminobenzonitrile and carboxylic acid were not found.In our study, most benzoic acid gave the desired quinazolines in good-to-high yields. However, para-methoxybenzoic gave lower yield compared to other benzoic acids, and it is possible that the strong electron-donating property of the MeO group reduces the reactivity of the benzoic acid. Heterocyclic aromatic acids were also suitable substrates for this reaction leading to desired quinazolines in moderate yields. Encouraged by the success with aromatic acids, aliphatic acids including N-Cbz-Lasparagine required for the synthesis of bleomycin analogs were studied. Aliphatic carboxylic acids are also suitable for this one-pot two-step reaction leading to 4-aminoquinazolines in good yields. To compare this new one-pot procedure against the conventional stepwise approach, phenylacetic acid was coupled with 2-aminobenzonitrile via its acyl chloride to give 2-N-(phenylacetyl) amino- benzonitrile in 72% yield; the resulting amide was subjected to the new one-pot two-step procedure and give compound in 54% yield. This indicates that preformation of the amide bond did not lead to higher yield of the desired 4-aminoquinazoline. More importantly, N-Cbz-Lasparagine reacted with 2-aminobenzonitrile to give 4-aminoquinazoline in good yield. 2-Aminobenzonitriles with halo groups reacted with either N-Cbz-L-asparagine or phenylacetic acid to give the desired products in moderate yields. The electron-withdrawing effects of the halo groups likely decreased the nucleophilicity of the aniline group, which may account for the observed lower yields.In chapter two, synthetic and mechanistic studies of Bleomycins were reviewed. The design of Bleomycin analogs was described. We got the starting material of Conformation-Restricted P-3A analogs with the one-pot two-step method, and tried to couple the side chain of peptide. A P-3A thiazole analog was designed and synthesized.Bleomycin is a clinically employed antitumor agent through the sequence-selective cleavage of DNA in a process that is both metal-iron and O2 dependent. However, dose-dependent undesired side effects, such as pulmonary toxicity, are limiting the therapeutic efficacy of bleomycins. Thus, it has been suggested that improved bleomycin analogs may have enhanced therapeutic index between anticancer activity and undesired toxicity. Each structural unit of bleomycin A2 contributes importantly to its biological activity: the N-terminal pyrimidine, the metal binding domain, demonstrated that the majority of the DNA binding affinity originates from the C-terminus with the bithiazole and the positively charged sulfonium salt. The role of the carbohydrate domain has been less extensively examined although it is known to enhance biological potency and efficacy.P-3A is a microbial product isolated in biosynthetic studies of the bleomycins, whose structure contains the functionalized pyrimidine core of bleomycin A2 and represents the simplest member of this class of agents. Boger detailed pioneering total syntheses of P-3A, and researched its SAR. Ohno et al. synthesized a serious of P-3A pymidine analogs and got a good biological activity.In medicinal chemistry, conformational restriction is commonly used to improve potency. We envisioned that the application of such a strategy to the metal-binding domain of bleomycin could lead to analogs that promote more efficient formation of the oxygen-Fe(II)-bleomycin complex. To test this concept, P-3A, the smallest member of the bleomycin family but still retaining DNA cleavage properties was selected. Therefore, the cyclization of the carbonyl group onto the 6-position of the pyrimidine nucleus was performed via a benzene ring. The quinazoline ring system should fix the–NH- group in a position that has higher propensity for metal binding compared with the relatively flexible amide group in P-3A and other bleomycins. We envisioned that 2-aminobenzonitrile could react with a carboxylic acid in an one-pot two-step procedure to produce the key intermediate required for our conformation-restricted P-3A analogs, and it can introduce the stereochemistry center with natural amino acid.We synthesized 2-amino-3-bromo-5-methylbenzonitrile via a five-step route, and got the key intermediate compound with it. We tried to couple the side chain of peptide via Buchwald coupling reaction and Ullmman-Type coupling reaction, but failed.In the design of the P-3A thiazole analog structure, the key groups of full metal binding domain in bleomycin structure was remained and P-3A thiazole analog was synthesized with three parts: serine segment, thiazole nuclear and side chain of two peptides. In synthesis routs, the ?-aminoalanine amide was synthesized via protecting amine with trityl, Mistunobu coupling with phthalimide, transforming trityl to Boc, amination of methyl, deporting the phthalimide with hydrazine. Thiazole nuclear was synthesized with ethyl bromopyruvate and ethanethioamide and then linked with serine segment. Finally, it coupled with peptide. We got the P-3A thiazole analog via a ten-step single route with a 25% total yield. And this P-3A thiazole analog can cleave supercoiled DNA at 200 ?M.