A regioselective synthetic route to 2,8-disubstituted pyrido[3,4-b]pyrazines, by initial condensation reaction between suitable diaminopyridines and alpha-keto aldehydes equivalents, has been developed. Focusing on the functionalization on C-8, 2-ary1-8-bromo- and 8-amino-2-arylpyrido[3,4-b]pyrazines have been synthesized. Anilines, amides, and ureas have been introduced at the 8-position from key intermediates. 2,8-Disubstituted pyrido[3,4-b]pyrazines thus prepared were found to be of biological interest.

AbstractAn efficient synthetic approach to the preparation of the title compounds (VIII) and (XVI) is developed.

A four-step synthesis of 8-bromo-2,3-disubstituted pyrido[3,4-b]pyrazines and a six-step synthesis of 8-amino-2,3-disubstituted pyrido[3,4-b]pyrazines have been developed. A particularly valuable feature of this synthetic route is the possibility to build 2,3-disubstituted pyrido[3,4-b]pyrazines with a large variety of substituents in position 8 (aniline, amide, urea, thiourea). Our protocol was extended to the synthesis of 2,3,8-trisubstituted pyrido[2,3-b]pyrazines.

The synthesis and study of the structure-activity relationships of cytotoxic compounds based on N-pyridinyl or N-aryl-2-(1-benzylindol-3-yl)glyoxamide skeleton, represented by the lead structures D-24241 and D-24851, are described. The presence of N-(pyridin-4-yl) moiety was crucial for activity and 2-[1-(4-chloro-3-nitrobenzyl)-1H-indol-3-yl]-2-oxo-N-(pyridin-4-yl)acetamide (55), the most potent derivative, showed IC(50)=39 nM, 51 nM and 11 nM against HeLa/KB (human cervix carcinoma), L1210 (murine leukemia) and SKOV3 (human ovarian carcinoma) cell lines proliferation assay, respectively, as active as the lead compounds.

New series of analogues of N-(pyridin-4-yl)-2-[1-(4-chlorobenzyl)-indol-3-yl]glyoxamide D-24851 were synthesized, characterized and tested for their in vitro anticancer properties. In the first series, an amino acid spacer was introduced in the glyoxamide chain of D-24851. In the second series, the glyoxamide chain was moved to positions 4 and 5 of indole skeleton. These new compounds were tested on four cancer cell lines (KB, SK-OV-3, NCI-H460 and SF-268), with promising activity for the glycine derivative.

Dihydropyrroloquinolines have been synthesized reacting 8-arylethynyl-1,2,3,4-tetrahydroquinolines in the presence of palladium(II) chloride catalyst. Heteroannulation has been achieved in good yields and tolerates substituents on the tetrahydroquinoline, including bromo, cyano, and ester.

Wstep : W duzych badaniach epidemiologicznych, takich jak Improvement czy EuroHeart Survey , realizowane takze w Polsce w latach 1999-2001, wykazano niedostateczne przestrzeganie wytycznych sformulowanych przez Europejskie Towarzystwo Kardiologiczne, dotyczących postepowania w niewydolności serca. Celem ostatnio zakonczonego badania byla aktualna ocena postepowania diagnostyczno-terapeutycznego, kosztow opieki oraz określenie dostepności do badan diagnostycznych i metod leczniczych w ośrodkach o roznym poziomie referencyjności. Celem niniejszej pracy jest przedstawienie zalozen i sposobu realizacji programu. Material i metody : Program realizowano w 2005 r. w ramach Narodowego Programu Profilaktyki i Leczenia Chorob Ukladu Krązenia (PolKARD). Badaniem objeto losowo dobraną probe ośrodkow podstawowej opieki zdrowotnej, poradni specjalistycznych, szpitali oraz wszystkie ośrodki kliniczne (akademickie). W kazdym z ośrodkow lekarz wypelnial ankiete dotyczącą postepowania diagnostyczno-terapeutycznego (na podstawie dokumentacji medycznej) u ostatnich 5 pacjentow z rozpoznaną niewydolnością serca, przyjetych podczas wizyty w gabinecie lub hospitalizowanych. Ponadto z jednym losowo wybranym pacjentem z danego ośrodka przeprowadzono wywiad, podczas rozmowy telefonicznej lub wizyty domowej. Badanie zrealizowano przy udziale pielegniarek zatrudnionych w charakterze ankieterow przez Pracownie Badan Spolecznych w Sopocie. Wyniki : Ogolem uzyskano 5275 ankiet na temat postepowania diagnostyczno-terapeutycznego od lekarzy podstawowej opieki zdrowotnej, specjalistow (kardiologow i internistow) oraz z oddzialow kardiologicznych i internistycznych z terenu calej Polski (efektywnośc: dane uzyskano z 99,5% ośrodkow spośrod rekrutowanych). Ponadto uzyskano dane bezpośrednio od 1024 pacjentow. Wnioski : Wyniki analiz z zakresu diagnostyki i leczenia pacjentow z niewydolnością serca posluzą do przedstawienia rozwiązan mających na celu poprawe obecnego modelu opieki w Polsce.

A human cDNA encoding the alpha subunit of casein kinase II and a partial cDNA encoding the rat homologue were isolated by using a Drosophila casein kinase II cDNA probe. The 2.2-kb human cDNA contains a 1.2-kb open reading frame, 150 nucleotides of 5' leader, and 850 nucleotides of 3' noncoding region. Except for the first 7 deduced amino acids that are missing in the rat cDNA, the 328 amino acids beginning with the amino terminus are identical between human and rat. The Drosophila enzyme sequence is 90% identical with the human casein kinase II sequence, and there is only a single amino acid difference between the published partial bovine sequence and the human sequence. In addition, the C-terminus of the human cDNA has an extra 53 amino acids not present in Drosophila. Northern analysis of rat and human RNA showed predominant bands of 5.5, 3.1, and 1.8 kb. In rat tissues, brain and spleen had the highest levels of casein kinase II alpha subunit specific RNA, while skeletal muscle showed the lowest. Southern analysis of human cultured cell and tissue genomic DNA using the full-length cDNA probe revealed two bands with restriction enzymes that have no recognition sites within the cDNA and three to six bands with enzymes having single internal sites. These results are consistent with the possibility that two genes encode the alpha subunits.