Antiproliferative Activity of N-Substituted 2,4-Diamino-5-Aryl-5,6,7,8,9,10-Hexahydrobenzo[B][1,8]Naphthyridine-3-Carbon
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Pharmaceutical Chemistry Journal, Vol. 54, No. 5, August, 2020 (Russian Original Vol. 54, No. 5, May, 2020)
ANTIPROLIFERATIVE ACTIVITY OF N-SUBSTITUTED 2,4-DIAMINO-5-ARYL-5,6,7,8,9,10-HEXAHYDROBENZO[B][1,8]NAPHTHYRIDINE-3-CARBONITRILES I. N. Bardasov,1,* A. Yu. Alekseeva,1 O. V. Ershov,1 and M. A. Mar’yasov1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 5, pp. 10 – 10, May, 2020.
Original article submitted March 30, 2020. Th antiproliferative activity of N-substituted 2,4-diamino-5-aryl-5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyridine-3-carbonitriles was studied. Substituents in the 5- and 7-positions of the naphthyridine ring had strong influences on the activity; in the 1-position, weak influences. Compounds with a C-5 3,4,5-trimethoxyphenyl radical were significantly superior to other derivatives. The influences of other substituents were not precisely established; however, a C-7 substituent played a key role in the manifestation of biological activity. Keywords: 1,8-naphthyridines, carbonitriles, malononitrile dimer, antiproliferative activity.
The development of medicines to battle oncological diseases is a modern scientific trend. Various classes of organic compounds, including naphthyridines and primarily the 1,8-isomer, are being scrutinized for new compounds [1 – 11]. Also, the presence of a carbonitrile in various classes of organic compounds is known to be capable of rendering them biologically active, in particular, antiproliferative [12 – 19]. The present work reports studies of the antiproliferative activity of N-substituted 2,4-diamino-5-aryl-5,6,7,8,9,10hexahydrobenzo[b][1,8]naphthyridine-3-carbonitriles that were previously synthesized by cascade heterocyclizations of malononitrile dimer and its ylidene-derivatives (Scheme 1) [20 – 23].
hydrobenzo[b][1,8]naphthyridine-3-carbonitrile (1a). A mixture of 2-chlorobenzaldehyde (0.141 g, 0.001 mol), piperidine (0.085 g, 0.001 mol), 2-[(3-oxocyclohex-1-en-1yl)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.272 g, 0.001 mol), and 2-aminopro-1-ene-1,1,3-tricarbonitrile (0.132 g, 0.001 mol) in EtOH (5 mL) was refluxed for 1 h. When the reaction was finished (TLC), the mixture was cooled. The precipitate was filtered off and rinsed with i-PrOH. Compounds 1b-f, 2a, and 2b were prepared analogously. EXPERIMENTAL BIOLOGICAL PART The biological target of naphthyridines is the colchicine-binding site on surface of division spindle microtubules responsible for separation of chromatids during mitosis [1, 2]. Interaction with this site inactivates topoisomerase II that controls and alters the topological states of DNA during transcription and replication. On the other hand, cyano groups tend to form H-bonds, the target of which can be DNA molecules themselves and amino-acid residues such as serine and arginine [24]. Binding to these amino acids disrupts the catalytic activity of several enzymes and destroys nitrogen exchange. The antiproliferative activity of cyano-substituted 1 and 2 was studied at the National Cancer Institute (U
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