Antitumor Agents. 3. Design, Synthesis, and Biological Evaluation of New Pyridoisoquinolindione and Dihydrothienoquinolindione Derivatives with Potent Cytotoxic Activity

Abstract

New antiproliferative compounds, the 1-aryl-3-ethoxycarbonyl-pyrido[2,3-g]isoquinolin-5,10-diones (PIQDs, 1-7), were designed on the basis of a molecular model obtained by aligning the common quinolinquinone substructure of 5H-pyrido[3,2-a]phenoxazin-5-one (PPH) and some known anticancer agents. A Diels-Alder reaction between quinolin-5,8-dione (QD) and a 2-azadiene, formed by demolition of 2-aryl-1,3-thiazolidine ethyl esters (T compounds), was used to produce 1-7 and the isomeric 1-aryl-3-ethoxycarbonylpyrido[3,2-g]isoquinolin-5,10-diones (8-14). Two other compounds, the 3-amino-3-ethoxycarbonyldihydrothieno[2,3-g]quinolin-4,9-dione (15) and the 3-amino-3-ethoxycarbonyldihydrothieno[3,2-g]quinolin-4,9-dione (16), arising from a 1,4 Michael reaction of QD with a thiolate species formed by opening of T compounds, were recovered from the reaction mixture. The antiproliferative activity of 1-16 was evaluated against representative human liquid and solid neoplastic cell lines. The IC(50) of these compounds had median values in the range 2.00-0.01 microM, with 2-4 and 15 exhibiting significantly higher in vitro cytotoxic activity. Compound 2, also evaluated against KB subclones (KB(MDR), KB(7D), and KB(V20C)), was shown to be scarcely subject to the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. The noncovalent DNA-binding properties of PIQDs were examined using UV-vis and (1)H NMR spectroscopy experiments. Accordingly, these compounds were confirmed to have an ability to intercalate into double-stranded DNA by topoisomerase I superhelix unwinding assay. Interesting structure-activity relationships were found. Three important features seem to contribute to the cytotoxic activity of these anticancer ligands: (i) the DNA intercalating capability of the three-cyclic quinonic system, typical of this class of compounds, (ii) the position of the pendant phenyl ring that, according to the superimposition model, must occupy the same area of the corresponding benzo-fused ring A of PPH, and (iii) the effect of electron-withdrawing substituents on the phenyl ring, which can contribute improving the pi-pi stacking interactions between ligand and DNA base pairs. Besides, a mechanism of action suspected to involve topoisomerases could be hypothesized to interpret the antiproliferative activity of the thienoquinolindione 15, which can be regarded as a cyclic cysteine derivative.

A class of novel carboline intercalators: Their synthesis, in vitro anti-proliferation, in vivo anti-tumor action, and 3D QSAR analysis

“…The DOCK scores of N-(3-benzyloxycarbonylcarboline-1-yl)ethylamino acid benzylesters are significantly higher than those of N-(3-carboxyl-9-benzylcarboline-1-yl)ethylamino acids. This comparison suggests that N-(3-benzyloxycarbonylcarboline-1-yl)ethylamino acid benzylesters may comfortably adopt the cavity of d(CGATCG) 2 and high DOCK score benefits the in vitro anti-proliferative and in vivo anti-tumor activities. As seen in Table 2, the IC 50 of N-(3-benzyloxycarbonylcarboline-1-yl)ethylamino acid benzylesters against HepG 2 and Hela cells range from 13.5 lM to more than 100 lM, while the IC 50 of N-(3-carboxyl-9-benzylcarboline-1-yl)ethylamino acids against HepG 2 and Hela cells range from 26.5 lM to more than 400 lM.…”

A class of Trp-Trp-AA-OBzl: Synthesis, in vitro anti-proliferation/in vivo anti-tumor evaluation, intercalation-mechanism investigation and 3D QSAR analysis

“…Docking of Trp-Trp-AA-OBzl toward d(CGATCG) 2 DNA intercalators have been widely noticed [9e11], and the LigandFit/LigandScore in DS Modeling2.1 and d(CGATCG) 2 (from Protein Data Bank, 1D12) have been widely used to carry out the automated docking studies of the intercalators [9e16]. To evaluate the possibility of Trp-Trp-AA-OBzl (4aet) as DNA intercalators an automated docking of 4aet toward the cavity of d(CGATCG) 2 was performed by following a general procedure, the DOCK scores were calculated and are listed in Table 1.…”

Novel N-(3-carboxyl-9-benzyl-β-carboline-1-yl)ethylamino acids: Synthesis, anti-tumor evaluation, intercalating determination, 3D QSAR analysis and docking investigation

“…The synthesis and anticancer activities of a numerous compounds that intercalate into DNA have been reported recently [7][8][9][10][11][12][13]. Some b-carboline alkaloids such as harmine and its derivatives, are highly cytotoxic against human tumor cell lines [14][15][16][17][18][19].…”