Bromal-derived tetrahydro-β-carbolines as neurotoxic agents: chemistry, impairment of the dopamine metabolism, and inhibitory effects on mitochondrial respiration

2-Hexanoyl-1-tribromomethyl-1,2,3,4-tetrahydro-β-carboline: Crystal Structure Analysis of a Potent Inhibitor of Complex I of Mitochondrial Respiration

“…Remarkably, out of a series of various other Nacylated highly halogenated tetrahydro-/?-carbolines investigated so far by X-ray crystallography [10,11,[12][13][14][15], this TaBro derivative 3 was found to be the only compound showing such a packing principle as described above. All the other related heterocycles (e.g., 2-trifluoroacetyl-TaBro [10] or 2-propanoyl-TaClo [13]) were also found to be ra cemic in the crystal, but being connected to each other by a single intermolecular hydrogen bond H(12) 0(15), thus forming an approximately lin ear zigzag chain, e.g.…”

“…All the other related heterocycles (e.g., 2-trifluoroacetyl-TaBro [10] or 2-propanoyl-TaClo [13]) were also found to be ra cemic in the crystal, but being connected to each other by a single intermolecular hydrogen bond H(12) 0(15), thus forming an approximately lin ear zigzag chain, e.g. for 2-trifluoroacetyl-TaBro parallel to [ 0 1 0 ].…”

“…Besides representing the most characteristic structural factors of 3, the 1-tribromomethyl group as well as the 7V-hexanoyl function have both been discussed to significantly contribute to the strong inhibitory capacity of this heterocycle towards mitochondrial respiration [10]. A presumable in volvement of this trihalogenmethyl moiety of 3 in the inhibitory action on complex I has to be taken into account due to the finding that acetaldehydederived tetrahydro-ß-carbolines affect mito- chondrial enzymes only moderately [6 , 7, 10].…”

“…Since the extent of lipophilicity of those 1 -trihalogenmethyl indol derivatives was found to distinctly favor their inhibitory capacity on complex I, we have synthesized a broad series of TaClo-and TaBro-related compounds for a comprehensive evaluation of their inhibitory po tential on the enzymes of mammalian mitochon drial respiration [6 , 10, 11]. Indeed, in the course of this work, the highly unpolar 2 -hexanoyll,2,3,4-tetrahydro-/3-carboline (3) turned out to be one of the most active agents displaying an even three times more effective inhibition (IC10o = ,«M) than its quite potent parent compound 2 ( I C joo -6 5 0 //M) [6,10]. In this paper, we report on the synthesis and X-ray diffraction analysis of 3 aiming at a more detailed knowledge concerning the three-dimensional structure of this tribromomethyl-substituted heterocycle.…”

Recentes aplicações sintéticas de compostos orgânicos tricloro(bromo)metila substituídos

“…4,5 Com relação aos derivados contendo o grupo -CBr 3 , destaca-se o agente neurotóxico 5. 6 Já o composto 6 é um dos componentes da alga vermelha Asparagopsis Taxiformis, que apresenta atividade contra aldose redutase em bovinos. 7 Aplicações sintéticas de compostos orgânicos contendo -CX 3 O desenvolvimento de novas estratégias e metodologias em sín-tese orgânica é um acontecimento recorrente e promissor de pesquisa em Química, e, nesse contexto, compostos orgânicos contendo o grupo -CX 3 (X = Cl, Br) têm sido citados na literatura como reagentes úteis e versáteis em diversas circuntâncias.…”