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Han X.,Peking Union Medical College | Zhang J.,Peking Union Medical College | Guo L.,Xinjiang Huashidan Pharmaceutical Co. | Cao R.,Xinjiang Huashidan Pharmaceutical Co. | And 6 more authors.
PLoS ONE | Year: 2012

Polo-like kinases play an essential role in the ordered execution of mitotic events and 4 mammalian PLK family members have been identified. Accumulating evidence indicates that PLK1 is an attractive target for anticancer drugs. In this paper, a series of beta-carboline derivatives were synthesized and three compounds, DH281, DH285 and DH287, were identified as potent new PLK inhibitors. We employed various biochemical and cellular approaches to determine the effects of these compounds on the activity of PLK1 and other mitotic kinases and on cell cycle progression. We found that these three compounds could selectively inhibit the kinase activity of purified PLK1, PLK2 and PLK3 in vitro. They show strong antitumor activity against a number of cancer cell lines with relatively low micromolar IC50s, but are relatively less toxic to non-cancer cells (MRC5). Moreover, these compounds could induce obvious accumulation of HeLa cells in G2/M and S phases and trigger apoptosis. Although MRC5 cells show clear S-phase arrest after treatment with these compounds, the G2/M arrest and apoptosis are less insignificant, indicating the distinct sensitivity between normal and cancer cells. We also found that HeLa cells treated with these drugs exhibit monopolar spindles and increased Wee1 protein levels, the characteristics of cells treated with PLK1 inhibitors. Together, these results demonstrate that DH281, DH285 and DH287 beta-carboline compounds are new PLK inhibitors with potential for cancer treatment. © 2012 Han et al.


Zhang G.,Sun Yat Sen University | Cao R.,Sun Yat Sen University | Guo L.,Xinjiang Huashidan Pharmaceutical Co. | Ma Q.,Xinjiang Huashidan Pharmaceutical Co. | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2013

A series of novel N2-alkylated quaternary β-carbolines was synthesized by modification of position-1, 2, 7 and 9 of β-carboline nucleus with various alkyl and arylated alkyl substituents, and their cytotoxic activities in vitro and antitumor potencies in mice were evaluated. Compound 3m was found to be the most potent antitumor agent. SARs analysis revealed that (1) the substituents in position-2 and 9 of β-carboline nucleus played a vital role in modulation of antitumor activity; (2) the benzyl and 3-phenylpropyl substituents in position-2 and 9 of β-carboline ring were the optimal substituents giving rise to significant antitumor agent. These compounds might be a novel promising class of antitumor agents with clinical development potential. © 2013 Elsevier Masson SAS. All rights reserved.


Shi B.,Sun Yat Sen University | Cao R.,Sun Yat Sen University | Fan W.,Xinjiang Huashidan Pharmaceutical Co. | Guo L.,Xinjiang Huashidan Pharmaceutical Co. | And 5 more authors.
European Journal of Medicinal Chemistry | Year: 2013

A series of bivalent β-carbolines with a spacer of three to ten methylene units between the indole nitrogen was synthesized and evaluated as antitumor agents. The results demonstrated that compounds 18c, 21b, 25a and 31b exhibited strong cytotoxic activities with IC50 value of lower than 20 μM against four tumor cell lines. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, compounds 18b, 21b, 26a and 31b exhibited potent antitumor activities with tumor inhibition rate of over 40% in animal models. Preliminary structure-activity relationships analysis indicated that (1) the spacer length affected antitumor potencies, and four to six methylene units were more favorable; (2) the introduction of appropriate substituent into position-1 of β-carboline facilitated antitumor potencies.


Wu Q.,Sun Yat Sen University | Bai Z.,Sun Yat Sen University | Ma Q.,Xinjiang Huashidan Pharmaceutical Co. | Fan W.,Xinjiang Huashidan Pharmaceutical Co. | And 6 more authors.
MedChemComm | Year: 2014

A series of novel bivalent β-carbolines with a spacer of three to ten methylene units between the 3-carboxyl oxygens was synthesized and evaluated as antitumor agents. The results demonstrated that most compounds displayed good and selective cytotoxic activities against 769-P and KB cell lines. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated. Compound 22 exhibited potent antitumor activity against Lewis lung cancer in mice with a tumor inhibition rate of 64.2%. Preliminary structure-activity relationship analysis indicated that (1) the length of the spacer affected cytotoxic activities in vitro and six methylene units were more favorable; (2) the introduction of substituents into position-1 of the β-carboline ring might be detrimental to antitumor potency in vivo models. © 2014 the Partner Organisations.


Chen Z.,China National Analytical Center | Cao R.,Sun Yat Sen University | Shi B.,Sun Yat Sen University | Guo L.,Xinjiang Huashidan Pharmaceutical Co. | And 4 more authors.
European Journal of Medicinal Chemistry | Year: 2011

A series of novel 1,9-disubstituted β-carbolines was designed, synthesized and evaluated as cytotoxic and DNA intercalating agents. Compounds 7b, 7c, 8b and 8c exhibited the most potent cytotoxic activities with IC 50 values of lower than 20 μM against ten human tumor cell lines. The results indicated that (1) the 3-chlorobenzyl and 3-phenylpropyl substituents in position-9 of β-carboline nucleus were the suitable pharmacophoric group giving rise to significant antitumor agents; (2) the length of the alkylamino side chain moiety affected their cytotoxic potencies, and three CH 2 units were more favorable. In addition, these compounds were found to exhibit remarkable DNA intercalating effects. © 2011 Elsevier Masson SAS. All rights reserved.


Chen Z.,Sun Yat Sen University | Cao R.,Sun Yat Sen University | Yu L.,Sun Yat Sen University | Shi B.,Sun Yat Sen University | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2010

In a continuing effort to develop novel β-carbolines endowed with better pharmacological profile, a series of water-soluble β-carbolines bearing a flexible amino side chain was designed and synthesized, and the cytotoxic activities in vitro of these compounds were evaluated. The N 9-arylated alkyl substituted β-carbolines represented the most interesting cytotoxic agents, and compounds 4c and 4d were found to be the most potent compounds with IC50 values lower than 10 μM against ten human tumor cell lines. The results confirmed that the N9-arylated alkyl substituents of β-carboline played a very important role in the modulation of the cytotoxic potencies. In addition, the interaction with DNA of these compounds was also investigated, these compounds were found to exhibit significant DNA binding affinity. © 2010 Elsevier Masson SAS. All rights reserved.


Ma C.,Sun Yat Sen University | Cao R.,Sun Yat Sen University | Shi B.,Sun Yat Sen University | Zhou X.,Sun Yat Sen University | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2010

The condensation of alkylenediamine with ethyl β-carboline-1- carboxylate and 1-bromo-β-carboline gave β-carboline-1-carboxamides and 1-amino-β-carbolines, respectively. Some of these β-carbolines were active against a panel of human tumor cell lines, and 1-amino derivatives were more potent than their 1-carboxamide congeners. In particular, among the 1-amino-β-carbolines, the N9-arylated alkyl substituted β-carbolines exhibited the most interesting cytotoxic activities with IC50 value of lower than 20 μM. The preliminary structure-activity relationships (SARs) analysis suggested that (1) 1-amino substituents were the advisable pharmacophoric group for enhanced cytotoxic activities; (2) the introduction of appropriate arylated alkyl groups into position-9 of β-carboline facilitated their cytotoxic potencies. © 2010 Elsevier Masson SAS. All rights reserved.


Cao R.,Sun Yat Sen University | Fan W.,Xinjiang Huashidan Pharmaceutical Co. | Guo L.,Xinjiang Huashidan Pharmaceutical Co. | Ma Q.,Xinjiang Huashidan Pharmaceutical Co. | And 5 more authors.
European Journal of Medicinal Chemistry | Year: 2013

Harmine, a naturally occurring β-carboline alkaloid, showed good antitumor activities together with remarkable neurotoxic effects in animal models. In order to search for novel leading compounds endowed with better antitumor activities and less neurotoxicities, a series of harmine derivatives were designed and synthesized by modification of position-2, 7 and 9 of β-carboline nucleus, and their cytotoxic activities against human tumor cell lines were investigated. Acute toxicities and antitumor activities of the selected compounds in mice were also evaluated. Structure-activity relationships studies confirmed that (1) the 7-methoxy structural moiety was the pharmacophore responsible for the neurotoxic effects of this class of compounds; (2) the substituents in position-2 and 9 played a vital role in modulation of their antitumor activities.


PubMed | Wuhan University, Sun Yat Sen University and Xinjiang Huashidan Pharmaceutical Co.
Type: | Journal: European journal of medicinal chemistry | Year: 2016

We have synthesized and evaluated a series of novel alkyl diamine linked bivalent -carbolines as potent angiogenesis inhibitors. The results demonstrated that most bivalent -carbolines exhibited significant antiproliferative effects against human umbilical vein cell lines EA.HY926. Compound 4m was found to be the most potent antiproliferative agent with IC


Gao P.,Xinxiang Medical University | Tao N.,CAS Institute of Biophysics | Ma Q.,Xinjiang Huashidan Pharmaceutical Co. | Fan W.-X.,Xinjiang Huashidan Pharmaceutical Co. | And 3 more authors.
Asian Pacific Journal of Cancer Prevention | Year: 2014

Aim: The purpose of this study was to investigate anti-tumor effects and safety of DH332, a new ß-carboline alkaloids derivatives in vitro and in vivo. Materials and Methods: The effects of DH332 on human (RAMOS RA.1) and mouse (J558) B lymphoma cell lines were detected using a CCK-8 kit (Cell Counting Kit-8), and apoptosis was detected by flow cytometry with PI/annexinV staining. Western blotting was used to detected caspase-3 and caspase-8. Neurotoxic and anti-tumor effects were evaluated in animal experiments. Results: DH332 exerts a lower neurotoxicity compared with harmine. It also possesses strong antitumor effects against two B cell lymphoma cell lines with low IC50s. Moreover, DH332 could inhibit the proliferation and induce the apoptosis of RAMOS RA.1 and J558 cell lines in a dose-dependent manner. Our results suggest that DH332 triggers apoptosis by mainly activating the caspase signaling pathway. In vivo studies of tumor-bearing BALB/c mice showed that DH332 significantly inhibited growth of J558 xenograft tumors. Conclusions: DH332 exerts effective antitumor activity in vitro and in vivo, and has the potential to be a promising drug candidate for lymphoma therapy.

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