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The New Unsaturated Acyclic C-5 Pyrimidine Nucleoside Analogues: Synthesis, Cytostatic And Anti-Hiv Evaluations


Gazivoda, Tatjana; Raić-Malić, Silvana; Kraljević-Pavelić, Sandra; Pavelić, Krešimir; Balzarini, Jan; Mintas, Mladen
The New Unsaturated Acyclic C-5 Pyrimidine Nucleoside Analogues: Synthesis, Cytostatic And Anti-Hiv Evaluations // Ninth Tetrahedron Symposium: Challenges in Organic and Bioorganic Chemistry / Martin, Stephen (ur.).
Berkeley: Elsevier, 2008. str. P1.98-P1.99 (poster, međunarodna recenzija, sažetak, znanstveni)


Naslov
The New Unsaturated Acyclic C-5 Pyrimidine Nucleoside Analogues: Synthesis, Cytostatic And Anti-Hiv Evaluations

Autori
Gazivoda, Tatjana ; Raić-Malić, Silvana ; Kraljević-Pavelić, Sandra ; Pavelić, Krešimir ; Balzarini, Jan ; Mintas, Mladen

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Ninth Tetrahedron Symposium: Challenges in Organic and Bioorganic Chemistry / Martin, Stephen - Berkeley : Elsevier, 2008, P1.98-P1.99

Skup
Ninth Tetrahedron Symposium: Challenges in Organic and Bioorganic Chemistry

Mjesto i datum
Berkeley, SAD, 22-25.07.2008

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Unsaturated acyclic C-5 pyrimidine nucleoside analogues; cytostatic evaluations; anti-HIV activities

Sažetak
Many nucleoside analogues with interesting biological properties have arisen by substitution at the 5-position of the uracil base in the 2'-deoxyuridine series.[1] Pyrimidine nucleosides containing C-5 alkynyl groups have been shown to possess significant antiviral and/or anticancer properties.[2] We have reported that some pyrimidines and purines containing gama-(Z)-ethylidene-2, 3-dibenzylbutenolide exhibited antiproliferative effects against malignant human tumor cell lines.[3] We have also reported that the (Z)-4-amino-2-butenyladenine nucleoside analogue showed selective activity against HIV-1.[4] The novel C-5 alkynyl pyrimidine nucleoside analogues (1-14) in which the sugar moiety was replaced by the conformationally restricted Z- and E-2-butenyl spacer between the phthalimido and pyrimidine ring were synthesized by using Sonogashira cross-coupling reaction (Scheme). Scheme: (i) NaH, DMF, argon atmosphere, r.t. ; (ii) R-C≡ CH, iPr2EtN, (PPh3)4Pd, CuI, DMF, r.t. The compounds 1-14 were evaluated for their cytostatic activities against malignant human tumor cell lines: murine leukemia (L1210), human T-lymphocyte (Molt4/C8 and CEM), cervical carcinoma (HeLa), pancreatic carcinoma (MiaPaCa-2), colorectal adenocarcinoma (SW 620), breast epithelial adenocarcinoma (MCF-7), hepatocellular carcinoma (Hep G2) and normal diploid human fibroblasts (WI 38), as well as for their inhibitory activities against HIV-1 and HIV-2 in human T-lymphocyte (CEM) cells. Compounds 3 and 4 showed some specific albeit slight activity against HIV-1 (3: EC50= 35 uM, 4: EC50= 10 uM), while compound 14 exhibited moderate activity against both HIV-1 (EC50= 14 uM) and HIV-2 (EC50= 3.1 uM). Cytostatic activity evaluation of the novel compounds showed that E-isomers (8-14) exhibited better cytostatic activities than the corresponding Z-isomers (1-7). REFERENCES 1. De Clercq, E. Nucleosides Nucleotides 1987, 6, 197. 2. Herdewijn, P. Antiviral Chem. Chemother. 1994, 5, 131 ; Beres, J., Bentrude, W.G., Balzarini, J., De Clercq, E., Otvos, L. J. Med. Chem. 1986, 29, 494. 3. Raić-Malić, S., Nagl, A., Pavelić, K., De Clercq, E., Mintas, M. J. Med. Chem. 1999, 42, 2673 ; ibid. J. Med. Chem. 2000, 43, 4806 ; Gazivoda, T., Plavec, J., Kraljević, S., Kralj, M., Pavelić, K. ; Balzarini, J., De Clercq, E., Mintas, M., Raić-Malić, S. Bioorg. Med. Chem. 2005, 13, 131 ; ibid. J. Med. Chem. 2007, 50, 4105 ; ibid. Bioorg. Med. Chem. 2007, 15, 749. 4. Krištafor, V., Raić-Malić, S., Pavelić, K., Balzarini, J., De Clercq, E. Bioorg. Med. Chem. 2006, 14, 8126

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti



POVEZANOST RADA


Projekt / tema
098-0982464-2393 - Molekularna obilježja miofibroblasta Dupuytrenove bolesti (Krešimir Pavelić, )
125-0982464-2922 - RAZVOJ NOVIH PROLIJEKOVA I LIJEKOVA PROTIV VIRUSA I RAKA (Mladen Mintas, )
125-0982464-2925 - Razvoj i primjena novih molekula u pozitron-emisijskoj tomografiji (PET) (Silvana Raić-Malić, )

Ustanove
Institut "Ruđer Bošković", Zagreb,
Fakultet kemijskog inženjerstva i tehnologije, Zagreb