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Pyrrolo[2,3-d]pyrimidine, also known as 7-deazapurine, is a heterocyclic system in several natural products and biologically active compounds.[1] Substituted pyrrolo[2,3-d]pyrimidines are of great importance for further development and synthesis of new derivatives as potent multiple receptor inhibitors, leading to the broad therapeutic application. Thus, the presence of pyrrolo[2,3-d]pyrimidine scaffold in many pharmaceuticals is not a surprising fact. Pyrrolo [2,3-d]pyrimidines represent the novel class of kinase inhibitors and folate-dependent enzyme inhibitors.[2,3] The folate-dependent enzyme inhibitors have found clinical utility as antitumor, antimicrobial, and antiprotozoal agents.[1] Multitargeted antifolate drug Pemetrexed also features the pyrrolo[2,3-d]pyrimidine ring system[4] and is used in therapy of lung cancer.[5] Furthermore, several 6-substituted pyrrolopyrimidines acted as inhibitors of dihydrofolate reductase (DHFR) [6,7] and thymidilate synthase[8], as well as antitumoral agents[9], while N-7 substituted pyrrolopyrimidines are inhibitors of tyrosine kinase.[10] It was also found that C-7 substituted 1,2,3-triazolyl-7-deazapurines posses cytostatic activities in nanomolar concentrations against lung and colon cancer cell lines in humans.[11] We expect that pyrrolo[2,3-d]pyrimidines will exhibit selective cytostatic activities. We also expect that conformational analysis will be helpful in further optimization of lead structures. Interdisciplinary collaboration of expert teams is prerequisite for successful achievement of main goals in proposed project: synthetic, medicinal and structural chemistry, molecular biology and medicine. Therefore, collaboration that includes frequent visits Croatian scientists in Slovenia and vice versa would provide additional implement of new knowledge and skills in synthesis and structural analysis of biologically active compounds. [1] C. J. Barnett et al. Tetrahedron Lett. 41 (2000) 9741. [2] H.S. Choi et al. Bioorg.Med. Chem. Lett. 16 (2006) 2173. [3] A.Gangjee et al. Bioorg. Med. Chem. 11 (2003) 5155. [4] C.Avendano et al. in Med. Chem. Anticanc. Drugs 2008, p.37. [5] A.A.Adjei Clin. Canc. Res. 10 (2004) 4276. [6] L.Wang et al. J. Med. Chem. 55 (2012) 1758. [7] A.Gangjee et al. J. Med. Chem. 47 (2004) 6893. [8] K.Aso et al. Chem. Pharm. Bull. 49 (2001) 1280. [9] E.C.Taylor et al. J. Org. Chem. 68 (2003) 9938. [10] H.S.Choi et al. Bioorg. Med. Chem.Lett. 16(2006)2173; ibid. 16(2006)2689. [11] A.B.Vourderioux et al. J. Med. Chem. 54 (2011) 5498.
Short description of the task performed by Croatian partner
The principle objective of this research project is development of new pyrrolo[2,3-d] pyrimidine derivatives with selective cytostatic activities. The following tasks will be carried out: 1) Synthesis of the novel pyrrolo[2,3-d]pyrimidine derivatives: The novel pyrrolo[2,3-d] pyrimidine derivatives will be prepared by multistep synthesis starting from C-2 substituted 4amino5iodopyrimidines. Aryl substituted alkynyl side chain will be introduced in to C-5 of pyrimidine ring by Sonogashira crosscoupling reaction, Pd-catalysed reaction for forming new C-C bond between aryl halogenides and terminal alkynes. C-6 substituted pyrrolo[2,3-d] pyrimidines will be synthesized in the next step by intramolecular cyclization of thus obtained C-5-alkynyl pyrimidine derivatives. Subsequent iodination of such pyrrolopyrimidines will yield precursors for new Sonogashira reaction, which will eventually lead to C-5 substituted bicyclic ring with aliphatic and aromatic substituents. Iodination of unsubstituted pyrrolopirimidines could give C-5 or C-6 regioisomers. In the last step of synthesis alkyne linkage will be transformed in 1,2,3-triazole in azide-alkyne „click“ reaction conditions, which is widely used in synthesis of pharmacologically active substances. 2) Structural characterization of newly prepared compounds: Structural analysis of all novel compounds will be carried out by 1H and 13C one- and two-dimensional NMR spectroscopy. The assignment of 1H and 13C NMR spectra will be performed on the basis of NMR chemical shifts, signal intensities, magnitude and multiplicity of H-H spin-spin coupling, as well as connectivities in twodimensional spectra COSY, HSQC, HMBC (homo- and heteronuclear H-H and H-C bond correlations), and NOESY (H-H dipol-dipol correlations). Conformational analysis will be also performed, especially for pyrrolopyrimidines with alkyne and triazole linkage, as well as determination of iodopyrimidines regioisomers from third step of the synthesis. 3) Cytostatic evaluations of newly prepared compounds: In vitro evaluation of new compounds against malignant human tumor cell lines (pancreatic, colon, cervical, breast, laryngeal carcinoma and T-lymphocites) and their cytotoxic activities will be performed in present collaboration with Department of Biotechnology, University of Rijeka (prof. dr. K. Pavelić, doc. dr. S. Kraljević Pavelić). 4) Structure-activity relationship: The compounds with most pronounced and selective activities will be used as lead compounds for further synthetic optimization for potential use in next phase of evaluation of biologically active antitumor compounds.
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