The cell division cycle 25 (CDC25) family of proteins is a group of highly conserved dual-specificity phosphatases. They are key regulators of normal cell division and the cell response to DNA damage, and play a fundamental role in transitions between cell cycle phases during normal cell division, via the activation of CdK/cyclin complexes. Their abnormal expression, detected in a number of tumors, often correlated with a poor clinical prognosis, implies that their dysregulation is involved in malignant transformation. Thus, inhibition of these proteins represents an attractive therapeutic target in oncology, as evidenced from many patents and papers published on the subject in recent years. Hence, this review aims to provide an overview of recent developments in the field of CDC25 phosphatase inhibitor design since 2008.

01 Sep 2009·Acta Pharmacologica SinicaQ1 · MEDICINE

LGH00031, a novel ortho-quinonoid inhibitor of cell division cycle 25B, inhibits human cancer cells via ROS generation

Q1 · MEDICINE

Article

Author: Jing-ya Li ; Yue-yang Zhou ; Yi Zang ; Hai-ping Yu ; Yu-bo Zhou ; Xu Feng ; Jun-qing Du ; Li-na Wang ; Jia Li

AIMTo discover novel cell division cycle 25 (CDC25) B inhibitors and elucidate the mechanisms of inhibition in cancer cells.METHODSCell growth inhibition was detected by MTT assay, the cell cycle was analyzed by flow cytometry, and protein expression and phosphorylation was examined by Western blot analysis.RESULTSLGH00031 inhibited CDC25B irreversibly in vitro in a dose-dependent manner, and impaired the proliferation of tumor cell lines. In synchronized HeLa cells, LGH00031 delayed the cell cycle progression at the G(2)/M phase. LGH00031 increased cyclin-dependent kinase 1 (CDK1) tyrosine 15 phosphorylation and cyclin B1 protein level. The activity of LGH00031 against CDC25B in vitro relied on the existence of 1,4-dithiothreitol (DTT) or dihydrolipoic acid and oxygen. The oxygen free radical scavenger catalase and superoxide dismutase reduced the inactivation of CDC25 by LGH00031, confirming that reactive oxygen species (ROS) mediate the inactivation process in vitro. LGH00031 accelerated cellular ROS production in a dose-dependent manner, and N-acetyl cysteine (NAC) markedly decreased the ROS production induced by LGH00031. Correspondingly, the LGH00031-induced decrease in cell viability and cell cycle arrest, cyclin B1 protein level, and phosphorylation of CDK1 tyrosine 15 were also rescued by NAC that decreased ROS production.CONCLUSIONThe activity of LGH00031 at the molecular and cellular level is mediated by ROS.

Khimiya Geterotsiklicheskikh Soedinenii

Syntheses based on 3H-benz[e]indole o-quinones

Author: Grinev, A. N. ; Sorokina, I. K.

Alkylatingthe title compounds I (R = H, Br; R¹ = H) by alkyl halides gave 20-85% I (R = H, R¹ = PhCH₂, p-BrC₆H₄COCH₂, PhCOCH₂; R = Br, R¹ = Me, PhCH₂, PhCOCH₂), which were cleaved by H₂O₂ to give 56-82% phenylpyrroles II (R = Br, R¹ = Me, PhCH₂; R = H, R¹ = PhCH₂).The latter were recyclized by heating in MeOH and treating with (CF₃CO)₂O to give 72-89% indenopyrroles III (same R, R¹).Treating I (R = Br, R¹ = Me, PhCH₂; R = H, R¹ = PhCH₂) with NBS gave 63-84% 2-bromomethyl derivatives, which underwent alkoxylation, hydroxylation, and amination.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	China	Shanghai Institute of Materia Medica Chinese Academy of Sci	04 Sep 2009

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