Synthesis and antitumor evaluation of some 1,3-disubstituted tetrahydropyrimido[4,5- c ]isoquinolines (original) (raw)
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Chemical & Pharmaceutical Bulletin, 2017
In this study, the pyrrolo[2,1-a] isoquinolines 4a-n were synthesized in good yields in a three steps synthesis from the corresponding α,β-unsaturated esters starting materials. These compounds were tested on six human cancer cells lines to measure the cytotoxic activity as a function of the electronic properties and aromaticity of the substituent at the C-2 position of the pyrroloisoquinoline. Our results reveal that the cytotoxic activity could be explained in terms of the distribution of electronic density across the ring joined to C-2. Also, this study identified 3-hydroxy (4d) and 3-chloro (4j) derivatives with powerful cytotoxic activities. The IC 50 values of these compounds were found to be comparable to those of the commercially available Topotecan, Irinotecan, Etoposide, Tamoxifen, and Cisplatin.
5,6-DIHYDROPYRROLO[2,1-A]ISOQUINOLINES as Alternative of New Drugs with Cytotoxic Activity
Chemical & pharmaceutical bulletin, 2017
In this study, the pyrrolo[2,1-a]isoquinolines 4a-n were synthesized in good yields in a three steps synthesis from the corresponding α,β-unsaturated esters starting materials. These compounds were tested on six human cancer cells lines to measure the cytotoxic activity as a function of the electronic properties and aromaticity of the substituent at the C-2 position of the pyrroloisoquinoline. Our results reveal that the cytotoxic activity could be explained in terms of the distribution of electronic density across the ring joined to C-2. Also, this study identified 3-hydroxy (4d) and 3-chloro (4j) derivatives with powerful cytotoxic activities The IC50 values of these compounds were found to be comparable to those of the commercially available Topotecan, Irinotecan, Etoposide, Tamoxifen, and Cisplatin.
Bioorganic & Medicinal Chemistry, 2011
A series of linear pyrrolo [1,2-b]isoquinoline derivatives was synthesized for antitumor evaluation. The preliminary antitumor studies reveal that both bis(hydroxymethyl) and their bis(alkylcarbamate) derivatives show significant antitumor activity in inhibiting various human tumor cell growth in vitro. 1,2-Bis(hydroxymethyl)-3-methyl-5,10-dihydropyrrolo[1,2-b]isoquinoline (20a) was selected for antitumor studies in animal models. The results show that this agent can induce complete tumor remission or significant suppression in nude mice bearing human breast (MX-1) xenograft and ovarian (SK-OV-3) xenografts, respectively. Alkaline agarose gel shifting assay showed that 20a is able to cross-link with DNA. Studies on the cell cycle inhibition revealed that this agent induces cell arrest at G2/M phase. The results warrant further antitumor investigation against other human tumor growth in animal models.
Synthesis and antitumor evaluation of 8-phenylaminopyrimido[4,5-c]isoquinolinequinones
Bioorganic & Medicinal Chemistry Letters, 2009
A series of 8-phenylaminopyrimido[4,5-c]isoquinoline-7,10-quinone derivatives were prepared by regioselective amination reaction of pyrimido[4,5-c]isoquinoline-7,10-quinones with arylamines in the presence of a Lewis acid catalyst. Preliminary evaluation of the members of the series against cancer cell lines and assays of activation of their cytotoxic activity on K562 cells with ascorbic acid are reported.
Molecules, 2012
A variety of novel 6-arylsubstituted benzo[j]phenanthridine-and benzo[g]pyrimido[4,5-c]isoquinolinequinones were synthesized from 1,4-naphthoquinone, arylaldehydes and enaminones via a two-step synthetic approach. The cytotoxic activity of the aminoquinone derivatives was evaluated in vitro against one normal cell line (MRC-5 lung fibroblasts) and three human cancer cell lines (AGS human gastric adenocarcinoma; SK-MES-1 human lung cancer cells, and J82 human bladder carcinoma) in 72-h drug exposure assays using the MTT colorimetric method. Structure-activity relationships within the series of angular quinones reveal that the insertion of pyrrol-2-yl and furan-2-yl groups at the 6-position is more significant for the increase of the potency and selectivity index of the pharmacophores.
Synthesis and Biological Activities of New Tetrahydroquinoline and Pyrimidine Derivatives
European Chemical Bulletin, 2019
A series of new tetrahydroquinoline derivatives (4a-j) were prepared by one-pot multicomponent, [4+2] cycloaddition route from 4aminonaphthalene, aromatic aldehydes and dihydrofurane (DHF) by using InCl3 catalyst under reflux temperature and also, pyrimidine derivatives (5a-n) were prepared by the same route from benzimidazole, aromatic aldehydes and maleic anhydride by using piperidine catalyst under ultrasonic irradiations. The synthesized tetrahydroquinoline and pyrimidine derivatives were characterized (IR, 1 H NMR, 13 C NMR). The synthesized tetrahydroquinoline and pyrimidine derivatives have been evaluated for antimicrobial, anti-tuberculosis and antiinflammatory activities.
2004
New antiproliferative compounds, the 1-aryl-3-ethoxycarbonyl-pyrido[2,3-g]isoquinolin-5,10diones (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, 10diones (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 µM, 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 π-π 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.
Synthesis of Some Novel 11b-Substituted Pyrimido[6,1-a]-isoquinoline Derivatives
Molecules, 2004
A series of novel 11b-substituted 1,6,7,11b-tetrahydropyrimido[6,1-a]isoquinoline-2,4-diones and 4-thioxo-1,3,4,6,7,11b-hexahydropyrimido[6,1-a]isoquinolin-2ones were synthesized, utilizing two alternative strategies for ring closure of tetrahydroisoquinoline intermediates obtained from N-phenethyl enaminones.
European Journal of Medicinal Chemistry, 2010
In the search of structureeactivity relationship studies and to explore the antitumor effect associated with the pyrimidoisoquinolinequinone scaffold, several diversily substituted 8-aminopyrimido[4,5-c] isoquinolinequinones were regioselectively synthesized. Variation in the structure of the nitrogen substituent bonded to the 8-position of the pyrimidoisoquinolinequinone system led to a set of alkylamino-, phenylamino-and alkyphenylamino derivatives. The cytotoxic activity of the aminoquinone derivatives was evaluated in vitro using the MTT colorimetric method against one normal cell line (MRC-5 lung fibroblasts) and four human cancer cell lines (AGS human gastric adenocarcinoma; SK-MES-1 human lung cancer cells, and J82 human bladder carcinoma; HL-60 human leukemia) in 72-h drug exposure assays. Among the series, five compounds exhibited interesting antitumor activity against AGS human gastric adenocarcinoma and human lung cancer cells. The SAR studies revealed that both the nature of the nitrogen substituent into the quinone ring and the methyl group at the 6-position play key roles in the antitumor activity.
Journal of the Chinese Chemical Society, 2017
Acetylation of 1-amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-phenyl carboxamide 3 afforded the corresponding tetrahydro[1,3]oxazinothieno[2,3-c]isoquinolinone compound 4. The oxazinone compound 4 underwent nucleophilic substitution reactions with various primary aliphatic and aromatic amines including some sulfa drugs such as sulfanilamide, sulfaguanidine, and sulfathiazole to afford the substituted pyrimidinone compounds 6-10. Chlorination of the pyrimidinone 10 with phosphorus oxychloride yielded the chloropyrimidine derivative 11. The latter compound was used as a versatile precursor for the synthesis of other heterocyclic rings containing the tetrahydropyrimidothienoisoquinoline moiety 12-23 through reaction with a variety of organic reagents. The newly synthesized compounds were fully characterized by elemental and spectral analyses, including melting point, TLC, and FT IR and 1 H NMR spectroscopy, as well as 13 C NMR and mass spectroscopy for most of them. These molecules should allow to us in the future to investigate their pharmacological activities.