Synthesis and Antitumor Activity of Thieno-Separated Tricyclic Purines

• Published in: Journal of medicinal chemistry Vol. 43; no. 25; pp. 4877 - 4883
• Main Authors: Seley, Katherine L, Januszczyk, Piotr, Hagos, Asmerom, Zhang, Liang, Dransfield, Daniel T
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.12.2000; Amer Chemical Soc
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Division - drug effects; Chemistry, Medicinal; Colorectal Neoplasms; Drug Screening Assays, Antitumor; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Purines - chemical synthesis; Purines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Pyrimidinones - chemical synthesis; Pyrimidinones - pharmacology; Science & Technology; Thiophenes - chemical synthesis; Thiophenes - pharmacology; Tumor Cells, Cultured; CONVENIENT SYNTHESIS; AZOLES; BENZOPURINES; NUCLEOTIDES; PROTECTING GROUP; DIMENSIONAL PROBES; RING-SYSTEM; IMIDAZOLES; ADENINE; BINDING-SITES; Antineoplastic agent; Human; Sulfur nitrogen heterocycle; Cell line; Lactam; Cytotoxicity; Colon; Tricyclic compound; Chemical synthesis; In vitro; Biological activity; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000326i

The purine ring system is undoubtedly one of the most ubiquitous heterocyclic ring systems in nature as it has the distinction of being the parent ring in countless derivatives of biological relevance. It is not surprising then that modified purines possess the potential to impact several areas, including a better understanding of the biological effects of DNA damaging agents, enzyme/substrate interactions, and in the development of more potent medicinal agents. One focus for our research at Georgia Tech has centered around the design and synthesis of a series of extended purine analogues containing a heterocyclic spacer ring, with sites set on investigations into their use as (i) potential anticancer and antiviral agents, (ii) dimensional probes for enzyme and coenzyme binding sites, and (iii) structural probes of the minor groove of DNA. The synthesis and preliminary antitumor activity of two thieno-separated purine analogues are described herein. Tricyclic 1 was synthesized in 12 steps from tribromoimidazole and with an overall yield of 7%. Tricyclic 2 was synthesized in 9 steps with an overall yield of 13%. Both 1 and 2 exhibited growth inhibitory effects on HCT116 colorectal cancer cells in vitro.