Institute Biopatologia y Medicina Regenerativa IBIMER

Las Rozas de Madrid, Spain

Institute Biopatologia y Medicina Regenerativa IBIMER

Las Rozas de Madrid, Spain
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Ramirez A.,Institute Biopatologia y Medicina Regenerativa IBIMER | Ramirez A.,University of Jaén | Morata-Tarifa C.,Institute Biopatologia y Medicina Regenerativa IBIMER | Morata-Tarifa C.,University of Granada | And 6 more authors.
Future Medicinal Chemistry | Year: 2017

Aim: Cancer is among the leading causes of death worldwide. Medical interest has focused on macrocyclic polyamines because of their properties as antitumor agents. Results/Methodology: We have designed and synthesized a series of 1,2-diaminocyclohexane derivatives with notable in vitro antiproliferative activities against the MCF-7, HCT-116 and A375 cancer cell lines. Cell cycle and apoptosis analyses were also carried out. Our results show that all the compounds are potent cytotoxic agents, especially against the A375 cell line. Conclusion: The selective activity of the macrocyclic derivative against A375, via apoptosis, supposes a great advantage for future therapeutic use. This exemplifies the potential of 1,2-diaminocyclohexane derivatives to qualify as lead structures for future anticancer drug development due to their easy syntheses and noteworthy bioactivity. © 2017 Future Science Ltd.


Cruz-Lopez O.,University of Granada | Ramirez A.,Institute Biopatologia y Medicina Regenerativa IBIMER | Ramirez A.,University of Jaén | Navarro S.A.,University of Granada | And 2 more authors.
Future Medicinal Chemistry | Year: 2017

Aim: Bozepinib is a potent and selective anticancer compound which chemical structure is made up of a benzofused seven-membered ring and a purine moiety. We previously demonstrated that the purine fragment does not exert antiproliferative effect per se. Methodology: A series of 1-(benzenesulfonyl)-4,1-benzoxazepine derivatives were synthesized in order to study the influence of the benzofused seven-membered ring in the biological activity of bozepinib by means of antiproliferative, cell cycle and apoptosis studies. Results & conclusion: Our results show that the methyleneoxy enamine sulfonyl function is essential in the antitumor activity of the structures and thus, it is a scaffold suitable for further modification with a view to obtain more potent antitumor compounds. © 2017 2017 Future Science Ltd.


Caba O.,University of Jaén | Caba O.,Institute Biopatologia y Medicina Regenerativa IBIMER | Rodriguez-Serrano F.,Institute Biopatologia y Medicina Regenerativa IBIMER | Ortiz R.,University of Jaén | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2012

Advance in the knowledge of molecular biology has thrown light on many aspects of apoptosis regulation mechanisms. This has allowed a change in anti-cancer therapy trends, from classic cytotoxic strategies to the development of new non-harmful therapies which target the apoptosis response selectively only in tumour cells. We have selected an anthranilic alcohol-derived acyclic 5-fluorouracil O,N-acetal (5) to carry out the anti-cancer studies. This compound shows activity as a potent growth inhibitor of the tumour cell line MCF-7 at a very low concentration. Moreover, when this compound was administered to the non-neoplastic cell line, MCF-10A displayed less toxicity resulting in lower rates of apoptosis. Further studies by microarray hybridization, real-time PCR and western blot showed that when administered to human breast cancer cells, MCF-7, 5 had no activity against classic pro-apoptotic genes such as p53, and even induced the down-regulation of anti-apoptotic genes such as Bcl-2. In contrast, several pro-apoptotic genes related with the endoplasmic reticulum (ER)-stress-induced apoptosis, such as BBC3 and Noxa, appeared up-regulated. These results seem to show that the mechanism of action and selectivity of 5 was via the activation of the ER stress-induced apoptosis. The selective activity of this compound against tumour cells via the ER stress-induced apoptosis supposes a great advantage for future therapeutic use. © 2012 Elsevier Masson SAS. All rights reserved.


Marchal J.A.,Institute Biopatologia y Medicina Regenerativa IBIMER | Ramirez A.,Institute Biopatologia y Medicina Regenerativa IBIMER | Garcia M.A.,Institute Biopatologia y Medicina Regenerativa IBIMER | Garcia M.A.,Universitario Virgen Of Las Nieves | Aranega A.,Institute Biopatologia y Medicina Regenerativa IBIMER
European Journal of Medicinal Chemistry | Year: 2011

Herein are reported the synthesis and anticancer activity against the human breast cancer cell line MCF-7 of a series of substituted (RS)-9-(2,3-dihydro-1, 4-benzoxathiin-2-ylmethyl)-9H-purine derivatives and (RS)-9-(2,3-dihydro-1,4- benzodioxin-2-ylmethyl)-9H-purine derivatives. When the Mitsunobu reaction was carried out between (RS)-2,3-dihydro-1,4-benzoxathiin-3-methanol and the heterocyclic bases 6-chloro-, 2,6-dichloro, and 6-bromo-purines under microwave-assisted conditions, a formal 1,4-sulfur migration takes place through two consecutive oxyranium and episulfonium rings, giving rise to the corresponding (RS)-9-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-9H-purine derivatives, previously reported by us. The most active compound (RS)-2,6-dichloro-9-(2,3-dihydro-1,4-benzoxathiin-2-ylmethyl)-9H-purine shows an IC 50 = 2.75 ± 0.02 μM. When the cancerous cells were treated with this compound, a significant increase of apoptotic cells (70.08 ± 0.33%) was obtained in relation to the control ones. The induction of the G 2/M cell cycle arrest and apoptosis by the three most active compounds is associated with increased phosphorylation of eIF2α in human breast cancer cells. © 2011 Elsevier Masson SAS. All rights reserved.


Caba O.,Institute Biopatologia y Medicina Regenerativa IBIMER | Rodriguez-Serrano F.,Institute Biopatologia y Medicina Regenerativa IBIMER | Boulaiz H.,Institute Biopatologia y Medicina Regenerativa IBIMER | Aranega A.,Institute Biopatologia y Medicina Regenerativa IBIMER | Marchal J.A.,Institute Biopatologia y Medicina Regenerativa IBIMER
European Journal of Medicinal Chemistry | Year: 2011

Completing a SAR study, a series of (RS)-6-substituted-7- or 9-(1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl)-7H or 9H-purines was previously prepared. The most potent antiproliferative agent against the MCF-7 adenocarcinoma cell line that belongs to the benzoxazepine O,N-acetalic family is (RS)-9-[1-(9H-fluorenyl-9-methoxycarbonyl)-1,2,3,5-tetrahydro-4,1- benzoxazepine-3-yl]-6-chloro-9H-purine (16, IC 50 = 0.67 ± 0.18 μM), whilst (RS)-7-{2-(N-hydroxymethylphenyl)-2-nitrobenzenesulfonamido]-1- methoxyethyl}-6-chloro-7H-purine (37) shows the lowest IC 50 value between the family of acyclic O,N-acetals (IC 50 = 3.25 ± 0.23 μM). Moreover, 16 showed the better in vitro Therapeutic Index in breast cell lines (3.19), whilst 37 was found to be 3.69-fold more active against HT-29 human colon cancer cell line than versus IEC-6 normal rat intestinal epithelial cell line. The global apoptotic cells caused by 16 and 37 against MCF-7 were 80.08% and 54.85% of cell population after 48 h, respectively. cDNA microarray technology reveals potential drug targets, which are mainly centred on positive apoptosis regulatory pathway genes, and the repression of genes involved in carcinogenesis, proliferation and tumour invasion. © 2011 Elsevier Masson SAS. All rights reserved.


Marchal J.A.,Institute Biopatologia y Medicina Regenerativa IBIMER | Boulaiz H.,Institute Biopatologia y Medicina Regenerativa IBIMER | Garcia M.A.,Institute Biopatologia y Medicina Regenerativa IBIMER | Garcia M.A.,Hospital Universitario Virgen Of Las Nieves | And 7 more authors.
European Journal of Medicinal Chemistry | Year: 2011

Completing an SAR study, a series of (RS)-6-substituted-7- or 9-(1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl)-7H or 9H-purines has been prepared under microwave-assisted conditions. Their antiproliferative activities on MCF-7 and MDA-MB-231 cancerous cell lines are presented, being the majority of the IC50 values below 1 μM. The most active compound (RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4, 1-benzoxazepin-3-yl]-9H-purine (14) presents an IC50 of 0.166 μM against the human cancerous cell line MDA-MB-231. Compound 14 was the most selective against the human breast adenocarcinoma MCF-7 and MDA-MB-231 cancer cell lines (Therapeutic Indexes, TIs = 5.1 and 11.0, respectively) in relation to the normal one MCF-10A. (RS)-14 was resolved into its enantiomers. Both enantiomers are equally potent, but more potent than the corresponding racemic mixture. (R)-14 induces apoptosis against MCF-7 up to 52.50% of cell population after 48 h, being more potent than the clinical-used drug paclitaxel (43%). (RS)-14 induces no acute toxicity in mice after two weeks of treatment.


Carrasco E.,Institute Biopatologia y Medicina Regenerativa IBIMER | Garcia M.A.,Hospital Universitario Virgen Of Las Nieves | Choquesillo-Lazarte D.,Instituto Andaluz Of Ciencias Of La Tierra Ugr Csic | Garcia-Ruiz J.M.,Instituto Andaluz Of Ciencias Of La Tierra Ugr Csic | Marchal J.A.,Institute Biopatologia y Medicina Regenerativa IBIMER
Current Medicinal Chemistry | Year: 2013

The issue of chiral drug is now a major theme in the design, discovery and development of new drugs. It has been shown for many pharmaceuticals that only one enantiomer contains the desired activity, and the synthesis of such drug molecules in their optically pure form is becoming increasingly important. Mitsunobu reaction was carried out between (R)- and (S)-3,4-dihydro-2H-1,5- benzoxathiepin-3-ol and purines under microwave irradiation. A contraction into a six-membered ring takes place with concomitant inversion at the stereocentre with excellent enatiomeric excesses giving rise to the homochiral 9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purines. The anti-tumour activity of all enantiomers is reported against the caspase-3-deficient MCF-7 and the wild type SKBR-3 human breast cancer cells. The most active homochiral compound displays an IC50 of 1.85 μM and induces inhibition of the translation initiation factor eIF2α. All homochiral compounds included in this study show different apoptotic effects between both enantiomers with levels up to 99%. We have analyzed caspase-mediated apoptotic pathways on enantiomers and racemates. We have found a homochiral derivative that activates the canonical intrinsic caspase-8/caspase-3 apoptotic pathway on the MCF-7 cells, and a racemic compound that induces caspase-2 activation. Moreover, we demonstrate the involvement of caspase activation during cell death induced by these compounds in SKBR-3 cells. © 2013 Bentham Science Publishers.


Chayboun I.,Abdelmalek Essaadi University | Boulifa E.,Abdelmalek Essaadi University | Mansour A.I.,Abdelmalek Essaadi University | Rodriguez-Serrano F.,Institute Biopatologia y Medicina Regenerativa IBIMER | And 4 more authors.
Journal of Natural Products | Year: 2015

The first enantiospecific syntheses of neopetrosiquinones A (6) and B (7), two merosesquiterpenes isolated from the deep-water sponge Neopetrosia cf. proxima, from the labdane diterpene trans-communic acid (10) have been achieved. A key step of the synthetic sequence is the simultaneous aromatization of the C ring and the benzylic oxidation on C-7 of an advanced intermediate, mediated by the oxygen-DDQ system. The in vitro antiproliferative activities of neopetrosiquinone B (7) and of the synthetic intermediates 8 and 9 against human breast (MCF-7), lung (A-549), and colon (T-84) tumor cell lines have been assayed. The most potent was compound 9 (IC50 = 4.1 μM), which was twice as active as natural compound 7 (IC50 = 8.3 μM) against A-549 cells. In addition, the treatment with these compounds resulted in an induction of apoptosis. These findings indicate that the terpene benzoquinones reported here might be potentially useful as anticancer agents. © 2015 The American Chemical Society and American Society of Pharmacognosy.


Morales F.,University of Granada | Ramirez A.,Institute Biopatologia y Medicina Regenerativa IBIMER | Ramirez A.,University of Jaén | Conejo-Garcia A.,University of Granada | And 3 more authors.
European Journal of Medicinal Chemistry | Year: 2014

As leads we took several benzo-fused seven- and six-membered scaffolds linked to the pyrimidine or purine moieties with notable anti-proliferative activity against human breast, colon and melanoma cancerous cell lines. We then decided to maintain the double-ringed nitrogenous bases and change the other components to the ethyl acetate moiety. This way six purine and two 5-fluorouracil derivatives were obtained and evaluated against the MCF-7, HCT-116, A-375 and G-361 cancer cell lines. Two QSARs are obtained between the anti-proliferative IC50 values for compounds 26-33 and the clog P against the melanoma cell lines A-375 and G-361. Our results show that two of the analogues [ethyl 2-(2,6-dichloro-9H- or 7H-purine-9- or 7-yl)acetates (30 and 33, respectively)] are potent cytotoxic agents against all the tumour cell lines assayed, showing single-digit micromolar IC50 values. This exemplifies the potential of our previously reported purine compounds to qualify as lead structures for medicinal chemistry campaigns, affording simplified analogues easy to synthesize and with a noteworthy bioactivity. The selective activity of 30 and 33 against the melanoma cell line A-375, via apoptosis, supposes a great advantage for a future therapeutic use. © 2014 Elsevier Masson SAS. All rights reserved.


PubMed | University of Jaén, Institute Biopatologia y Medicina Regenerativa IBIMER and University of Granada
Type: | Journal: European journal of medicinal chemistry | Year: 2014

As leads we took several benzo-fused seven- and six-membered scaffolds linked to the pyrimidine or purine moieties with notable anti-proliferative activity against human breast, colon and melanoma cancerous cell lines. We then decided to maintain the double-ringed nitrogenous bases and change the other components to the ethyl acetate moiety. This way six purine and two 5-fluorouracil derivatives were obtained and evaluated against the MCF-7, HCT-116, A-375 and G-361 cancer cell lines. Two QSARs are obtained between the anti-proliferative IC values for compounds 26-33 and the clog P against the melanoma cell lines A-375 and G-361. Our results show that two of the analogues [ethyl 2-(2,6-dichloro-9H- or 7H-purine-9- or 7-yl)acetates (30 and 33, respectively)] are potent cytotoxic agents against all the tumour cell lines assayed, showing single-digit micromolar IC values. This exemplifies the potential of our previously reported purine compounds to qualify as lead structures for medicinal chemistry campaigns, affording simplified analogues easy to synthesize and with a noteworthy bioactivity. The selective activity of 30 and 33 against the melanoma cell line A-375, via apoptosis, supposes a great advantage for a future therapeutic use.

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