Research progress on the biological activity of pyrrole 1,2-α indole alkaloids / 中国基层医药

Pyrrole [1,2-α] indole is a novel fused heterocyclic skeleton, which is also the basic structural unit and synthetic intermediate of many natural active products and drugs. Pyrrole [1,2-α] indole heterocyclic derivatives have attracted much attention in organic synthesis and medicinal chemistry because of their extensive and marked biological activities. Plant extracts have always been an important source of active compounds. At present, the alkaloids based on the pyrrole [1,2-α] indole heterocyclic structure discovered and isolated from plant extracts include isatisine, isoborreverine, flinderoles, polyavolensin and yuremamine. This paper reviews the research progress on the biological activity of pyrrole [1,2-α] indole heterocyclic derivatives and has found that pyrrole [1,2-α] indole heterocyclic derivatives have a good development prospect in screening active compounds and developing candidate drugs.

Design and synthesis of imidazo-fused heterocycles derivatives and their anti-tumor activity against breast cancer in mice / 南方医科大学学报

<p><b>OBJECTIVE</b>To synthesize compounds based on imidazo-fused heterocycles and evaluate their anti-tumor activity against breast cancer.</p><p><b>METHODS</b>The compounds 1a-1e, 2a and 2b were synthesized by aerobic copper-catalyzed halocyclization of methyl N-heteroaromatics with aliphatic amines; 3a and 3b were generated by sonogashira reaction and Suzuki reaction, respectively; the compounds 4a-4c were obtained by Buchwald-Hartwig reaction of the corresponding amines and 1e. The effects of these compounds against breast cancer cells and their nephrotoxicity were determined using MTT assay. Annexin VFITC/PI apoptosis detection kit was used to assess the apoptosis-inducing effects of these compounds in breast cancer cells. With normal saline as the control, the safety and anti-tumor activity of the compound 2a (daily dose of 10 mg/kg for 14 days) was tested in a mouse model bearing human breast cancer xenografts.</p><p><b>RESULTS</b>The compounds 2a, 4a, 4b and 4c all showed obvious anti-tumor activities. Among these compounds, 2a showed the most potent anti-tumor effect against breast cancer cells with an IC of 9.77 ± 2.32 μmol/L, similar to that of cisplatin (IC=8.96 ± 2.35 μmol/L); 2a also showed a slightly lower nephrotoxicity than cisplatin, and their CC was 10.79±0.87 μmol/L and 8.45±0.68 μmol/L, respectively. 2a obviously promoted apoptosis of breast cancer cells and caused a moderate suppression of the breast cancer growth in the tumor-bearing mouse models without producing serious adverse effects.</p><p><b>CONCLUSIONS</b>Four compounds synthesized based on imidazo-fused heterocycles have anti-tumor activities against breast cancer. The compound 2a is capable of dose-dependently promoting apoptosis of breast cancer cells and has a good safety and a moderate efficacy for suppressing tumor growth in mouse models bearing human breast cancer xenografts.</p>

Síntese e funcionalização de compostos organoenxofre: sulfóxidos, sulfetos e N-sulfinil iminas / Synthesis and functionalization of organosulfur compounds: sulfoxides, sulfides and N-sulfinyl imines

Neste trabalho promovemos a síntese de sulfóxidos vinílicos ?-substituídos através da reação de acoplamento cruzado de Suzuki-Miyaura. Também foi feita a síntese de sulfóxidos enínicos inéditos, pela adição do nucleófilo no carbono ß-sulfóxido. Esses compostos eram passíveis de serem submetidos a reação de rearranjo de Pummerer aditivo e assim gerarem uma pequena biblioteca de compostos α-tioaldeídos. Um desses aldeídos sintetizados foi empregado na reação de formação de uma imina propargílica, com consequente reação de CuAAC formando iminas triazólicas. Outras iminas arílicas foram sintetizadas, passando por uma etapa de redução, com intuito de se obter a amina livre, para que fosse feita a reação de ciclização com auxílio de um agente eletrofílico. Outra classe de composto organoenxofre foi sintetizada, as N-sulfinil imina, que após a reação de acoplamento cruzado de Sonogashira, com consequente remoção de um grupo protetor e a formação do anel heterocíclico, foram obtidos compostos triazólicos N-sulfinil imínicos.

In this work we promote the synthesis of α-substituted vinylic sulfoxides through the Suzuki-Miyaura cross coupling reaction. Also the synthesis of unpublished enynic sulfoxides was made, by the addition of the nucleophile in the ß-sulfoxide carbon. These compounds were susceptible to additive Pummerer rearragement reaction and thus generated a small library of compounds. One of these aldehydes synthesized was used in the formation reaction of a propargyl imine, with consequent CuAAC reaction, forming triazol imines. Other aryl imines were synthesized, undergoing a reduction step, in order to obtain the free amine, so that the cyclization reaction was carried out with the aid of an electrophilic agent. Another class of organosulfur compound was synthesized, the N-sulfinyl imine, which after the Sonogashira cross-coupling reaction, with consequent removal of a protecting group and formation of the heterocyclic ring, N-sulfinyl imine triazolic compounds were obtained.

Structural optimization and biological evaluation of 1,5-disubstituted pyrazole-3-carboxamines as potent inhibitors of human 5-lipoxygenase

Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1 µmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused-ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders.

Synthesis and antitumor activity of fluoroquinolone C-3 fused heterocyclic thiazolo3, 2-b 1, 2, 4triazole derivatives (VI) / 中国药学杂志

OBJECTIVE: To discover an efficient strategy for conversion of the antibacterial activity of fluoroquinolone drugs to antitumor activity. METHODS: Novel title fused heterocyclic C-3 thiazolo[3,2-6] [1,2,4] triazole derivatives(5,6) were designed by using a s-triazole ring as the bioisostere and modifying it by a fused condensation-cyclization reaction. The structures were validated by elemental analysis and spectral data, and the in vitro antitumor activity of the title compounds against three tested tumor cell lines was evaluated by MTT assay. RESULTS: Twelve title compounds were synthesized from ofloxacin and exhibited more significant antiproliferative activity than both of parent ofloxacin 1 and the corresponding intermediate sulfide ketones 5, but displayed a slightly weaker activity than the corresponding sulfide ketone thiosemi-carbazones 6. CONCLUSION: An efficient structure modification strategy for the fused heterocyclic core of thiazolotriazole used as the C-3 bioisostere warrants further development.