4-hydroxy-3-methoxyphenyl substituted 3-methyl-tetrahydroquinoline derivatives obtained through imino diels-alder reactions as potential antitumoral agents

Letters in Drug Design and Discovery

Volumn 7, Issue 9, 2010, Pages 632-639

  Kouznetsov, Vladimir V ^a   Arenas, Diego R Merchan ^a   Arvelo, Francisco ^b   Forero, Josué S Bello ^a   Sojo, Felipe ^b   Muñoz, Arturo ^b  

^a UNIVERSIDAD INDUSTRIAL DE SANTANDER   (Colombia)

^b FACULTAD DE CIENCIAS   (Venezuela)

Author keywords

Antitumoral agents; Functionalized tetrahydroquinolines; Isoeugenol; Lewis acid catalyzed imino diels alder reactions

Indexed keywords

2 ARYL 4 (4 HYDROXY 3 METHOXYPHENYL) 3 METHYLTETRAHYDROQUINOLINE; 4 HYDROXY 3 METHOXYPHENYL 3 METHYL TETRAHYDROQUINOLINE DERIVATIVE; ANTINEOPLASTIC AGENT; DIHYDROSPIRO[INDOLINE 3,2' QUINOLIN] 2 ONE DERIVATIVE; IMINO ACID; ISOVANILLIN; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; CYTOTOXICITY; DIELS ALDER REACTION; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; PRIORITY JOURNAL; SUBSTITUTION REACTION; TUMOR GROWTH;

EID: 77958538548     PISSN: 15701808     EISSN: None     Source Type: Journal    
DOI: 10.2174/157018010792929577     Document Type: Article

References (30)

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26. Process cycloaddition was highly diastereoselective, furnishing r- Me-trans-2-Ar-trans-4-guayacoyl-THQ isomers. All these diastereoisomers were stable solid substances, 1H-NMR and 13CNMR analysis of these tetrahydroquinoline products indicated that the structure of major diastereoisomer 4-12 was cis-(2e,4e)-form (given in the Scheme 1). The large vicinal coupling constants J2a,3a and J3a,4a = 9.9-11.0 Hz for this form indicate an axial-axial (trans) relationship and the aryl groups on C-2 (ring C) and C-4 (ring D) are both pseudo-equatorial and are located in cis-configuration.
27. The 1H-NMR and 13C-NMR analysis of the DSQ indicated that the methyl substituent in position C-3́ was trans to the aryl ring at C- 4́(ring D) of the major diastereoisomer 16-23 having trans- (3́e,4́e)-form (shown in Scheme 2). This was corroborated by the tetrahydroquinoline protons H-3́ and H-4́ coupling constants (J3́a,4́a = 11.2-11.9 Hz), affirmation enough to indicate the axialaxial (trans) relationship to the case.
28. Human tumour cell lines and media: PC3 (Prostate carcinoma), HeLa (Cervical epithelial carcinoma) were grown in RPMI 1640 medium (Invitrogen) supplemented with 10% heat inactivated fetal bovine serum (FBS), 1% of L-glutamine, 1% streptomicyn, 100 units/mL penicillin (all obtained from Sigma Aldrich USA). MCF- 7 (breast carcinoma, no overexpresses the HER2/c-erb-2 gene), SK-BR-3 (breast carcinoma, overexpresses the HER2/c-erb-2 gene) and primary culture of normal human dermis fibroblast used as control cells were grown in DMEM medium (Invitrogen). Cells were grown in a humidified incubator with 5% CO2 and 95% air at 37C until they reach the exponential growth phase. For treatments exponentially growing cells were collected, counted, re-suspended in fresh culture medium and incubated in 96 sterile well plates.
29. Cell viability by MTT assay: The effect of all the tetrahydroquinoline compounds was assessed using the standard MTT (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay described by Mosmann (Mosmann, T. J. Inmunol. Methods, 1983, 65, 55-63). Briefly, the cells were plated at 5x104 cells per well in 200μL of complete culture medium containing 0, 1, 5, 10, 25, 50 μg/mL concentrations each one compounds in 96 well microtiter plates for 24, 48 and 72 hours at 37C in a humidified incubator. At the end of the incubation, MTT (0.50 mg/mL in phosphate buffered saline) was added to each well and the plates were incubated for 4 h at 37C. Then, the plates were centrifuged at 1800 g for 5 min. and washed with PBS to remove excess of MTT. Finally, the formazan crystals were dissolved with DMSO and the plates were read by a microplates reader at 570 nm. The effect of all the compounds on growth inhibition was assessed as per cent cell viability where vehicle-treated cells were taken a 100% viable. The IC50 value was defined as the concentration of compound required to induce a 50% reduction of absorbance as compared to control, nontreated cells. Adriamycin was used as a positive control in the assay. In all cases the compounds were dissolved in DMSO, at the final concentration in the culture medium was lower than 1%, a concentration that had neither cytotoxic effect nor caused any interference with the colorimetric detection method.
30. Statistical Analysis: All experiments were performed at least three times. The results are expressed as mean ± SD. Anova test were performed. Only post hoc Dunnet test p < 0.01 was considered to be statistically significant. The values of IC50 were determined by a non-linear regression of individual experiments using the program Graph Pad Prism (Intuitive Software for Science, San Diego, CA, USA).