- Multicomponent synthesis of some new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro anti-proliferative activity against CaSki, MDA-MB-231 and SK-Lu-1 tumour cells as apoptosis inducing agents without necrosis
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Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound 9e also exhibited greater tumor selectivity than human lymphocytes. In silico ADME predictions revealed that compound 9e has the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile.
- Laskar, Sujay,Sánchez-Sánchez, Luis,López-Ortiz, Manuel,López-Mu?oz, Hugo,Escobar-Sánchez, María L.,Sánchez, Arturo T.,Regla, Ignacio
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p. 1129 - 1135
(2017/09/18)
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- Chemoenzymatic synthesis and cannabinoid activity of a new diazabicyclic amide of phenylacetylricinoleic acid
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Endocannabinoids (eCBs) are endogenous neuromodulators of synaptic transmission. Their dysfunction may cause debilitating disorders of diverse clinical manifestation. For example, drug addiction, lack of sex desire, eating disorders, such as anorexia or bulimia and dyssomnias. eCBs also participate in the regulation of core temperature and pain perception. In this context, it is important to recognize the utility of cannabinoid receptor 1 (CB1R) agonists, natural as Δ9-tetrahydrocannabinol (THC) or synthetic as Nabilone as useful drugs to alleviate this kind of patients' suffering. Therefore, we have developed a new drug, (R,Z)-18-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-18-oxooct adec-9-en-7-yl phenylacetate (PhAR-DBH-Me), that appears to bind and activate the CB1R. This diazabicyclic amide was synthesized from phenylacetylricinoleic acid and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane. To test its cannabinergic properties we evaluated its effects on core temperature, pain perception, and the sleep-waking cycle of rats. Results indicate that 20 and 40 mg/kg of PhAR-DBH-Me readily reduced core temperature and increased pain perception threshold. In addition, 20 mg/kg increased REM sleep in otherwise normal rats. All these effects were prevented or attenuated by AM251, a CB1R antagonist. Place preference conditioning studies indicated that this molecule does not produce rewarding effects. These results strongly support that PhAR-DBH-Me possesses cannabinoid activity without the reinforcement effects.
- López-Ortíz, Manuel,Herrera-Solís, Andrea,Luviano-Jardón, Axel,Reyes-Prieto, Nidia,Castillo, Ivan,Monsalvo, Ivan,Demare, Patricia,Méndez-Díaz, Mónica,Regla, Ignacio,Prospéro-García, Oscar
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scheme or table
p. 3231 - 3234
(2010/10/02)
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- Synthesis of novel derivatives of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane and their evaluation as potential ligands in asymmetric catalysis
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Thirty-seven (most of them novel) chiral derivatives of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane (2-36, 38, 39) were prepared from (S)-trans-4-hydroxyproline. A selection of these chiral ligands were examined as potential ligands in the preparation of catalysts for the enantioselective addition of diethylzinc to aldehydes and as chiral Lewis acid activators in the asymmetric Diels-Alder reaction. In the former system, diamine 30 induced up to 92 % enantiomeric excess in the formation of (S)-phenyl ethyl carbinol, whereas in the case of the cycloaddition reaction between cyclopentadiene and 3-acryloyloxazolidin-2-one the catalytic complex formed between dimeric derivative 8 and copper triflate [Cu(OTf)2] afforded the expected product in a 95:5 endo/exo ratio and up to 72 % ee for the major diastereomeric product. Finally, some of the novel chiral diamines prepared in this work were also evaluated as potential organocatalysts in the asymmetric amination of ethyl α-phenyl-α-cyano acetate. Bifunctional derivative 12 provided the animated product in excellent yield and with up to 40 % ee. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Melgar-Fernandez, Roberto,Gonzalez-Olvera, Rodrigo,Olivares-Romero, J. Luis,Gonzalez-Lopez, Vianney,Romero-Ponce, Leticia,Ramirez-Zarate, Maria Del Refugio,Demare, Patricia,Regla, Ignacio,Juaristi, Eusebio
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p. 655 - 672
(2008/09/17)
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- Preparation of 2,5-diazabicyclo[2.2.1]heptanes and intermediates
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(R,R)-2,5-Diazabicyclo[ 2.2.1]heptanes are prepared from a compound of the formula STR1 wherein X and R2 are as defined herein, by heating with tosylchloride in pyridine, reacting the formed compound of the formula STR2 with a C1 -C6 alkylamine or ammonia, and reducing or hydrolyzing the formed compound of the formula STR3 wherein R1 is hydrogen or C1 -C6 alkyl.
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- 1-indolyalkyl-4-(substituted-pyridinyl)piperazines
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A series of 1,4-disubstituted piperazine derivatives comprised of indol-3-ylalkyl and substituted pyridin-2-yl substituent groups. These compounds are useful as antidepressant agents.
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- Rhodium complexes of chiral phosphines
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Novel chiral phosphines are disclosed which when complexed with rhodium provide catalyst compositions for asymmetric hydrogenations.
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