Development of 3-aryl-1-isoquinolinamines as potent antitumor agents based on CoMFA

Yang, Suhui; Van, Hue Thi My; Le, Thanh Nguyen; Khadka, Daulat Bikram; Cho, Suk Hee; Lee, Kyung Tae; Lee, Eung Seok; Lee, Young Bok; Ahn, Chang Ho; Cho, Won Jea

doi:10.1016/j.ejmech.2010.08.042

Cited by 21 publications

(6 citation statements)

References 14 publications

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“…Given the reduced effect of FX-9 on slower proliferating benign cells, as well as the clear impact on cell cycle (induction of apoptosis during proliferation, G2/M phase enrichment and formation of multinucleated cells), FX-9 induces its anti-cancer effects in an anti-mitotic manner. Induced G2/M-phase cell cycle arrest has been shown for some isoquinolinamine agents already [24,25,26] partly due to tubulin polymerization inhibition. Prolonged mitotic arrest will eventually lead to cell death by apoptosis as detected for the PCa cell lines exposed to FX-9.…”

Section: Discussionmentioning

confidence: 99%

“…Amino-substituted isoquinoline structures are considered as tracers in positron emission tomography (PET) imaging [17,18,19] but also show a broader range of inhibitory [20,21,22] and cytotoxic effects e.g., activity against fungi [21], malaria [23], and cancer [22,24,25,26]. Recently, our group showed that novel synthesized isoquinolinamine FX-9 inhibits proliferation and induces apoptosis in human B- and T-acute lymphoblastic leukemia (ALL) cell lines, but displays no hemolysis on erythrocytes or cytotoxicity against non-neoplastic leukocytes.…”

Section: Introductionmentioning

confidence: 99%

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Isoquinolinamine FX-9 Exhibits Anti-Mitotic Activity in Human and Canine Prostate Carcinoma Cell Lines

Schille

Nolte

Packeiser

et al. 2019

IJMS

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Current therapies are insufficient for metastatic prostate cancer (PCa) in men and dogs. As human castrate-resistant PCa shares several characteristics with the canine disease, comparative evaluation of novel therapeutic agents is of considerable value for both species. Novel isoquinolinamine FX-9 exhibits antiproliferative activity in acute lymphoblastic leukemia cell lines but has not been tested yet on any solid neoplasia type. In this study, FX-9′s mediated effects were characterized on two human (PC-3, LNCaP) and two canine (CT1258, 0846) PCa cell lines, as well as benign solid tissue cells. FX-9 significantly inhibited cell viability and induced apoptosis with concentrations in the low micromolar range. Mediated effects were highly comparable between the PCa cell lines of both species, but less pronounced on non-malignant chondrocytes and fibroblasts. Interestingly, FX-9 exposure also leads to the formation and survival of enlarged multinucleated cells through mitotic slippage. Based on the results, FX-9 acts as an anti-mitotic agent with reduced cytotoxic activity in benign cells. The characterization of FX-9-induced effects on PCa cells provides a basis for in vivo studies with the potential of valuable transferable findings to the benefit of men and dogs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Isoquinolinamine FX-9 Exhibits Anti-Mitotic Activity in Human and Canine Prostate Carcinoma Cell Lines

Schille

Nolte

Packeiser

et al. 2019

IJMS

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“…Compounds 3c , 3e – i , 3k , 3n – o , 3ag – 3ai , 3ig , 3pg , and 3al are also new compounds. The skeleton of 3-aryl-1-aminoisoquinolines has been found to have biological activities against cancer, tumor, inflammatory, and Parkinson’s disease . Our method provides a concise approach to the bioactive chemical scaffold, extending the vision of drug discovery.…”

Section: Resultsmentioning

confidence: 99%

Regioselective Access to 3-Aryl-1-aminoisoquinolines via Nickel(I)-Catalyzed C–C and C–N Cascade Coupling Reactions from the Substituted 2-(Cyanomethyl)benzonitriles

Yang

et al. 2018

J. Org. Chem.

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“…FX-9 (3-(p-Tolyl)isoquinolin-1-amine) is a synthesized amino-substituted isoquinoline [ 1 ]. Agents of this substance family are antimalarial [ 2 ], antifungal [ 3 ] and active against different tumors [ 4 – 6 ]. In previous studies, we were able to demonstrate that FX-9 shows an antiproliferative effect on lymphoblastic leukemia cells, inducing morphological changes and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of combination protocols of the chemotherapeutic agent FX-9 with azacitidine, dichloroacetic acid, doxorubicin or carboplatin on prostate carcinoma cell lines

et al. 2021

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The isoquinolinamine FX-9 is a novel potential chemotherapeutic agent showing antiproliferative effects against hematologic and prostate cancer cell lines such as B- and T-acute lymphoblastic leukemia and prostate cancer (PC) of different species. Interestingly, FX-9 shows no hemolytic activity and low toxicity in benign adherent cells. The detailed FX-9 molecular mode of action is currently not fully understood. But application on neoplastic cells induces pro-apoptotic and antimitotic effects. Canine prostate cancer (cPC) represents a unique spontaneous occurring animal model for human androgen-independent PC. Human androgen-independent PC as well as cPC are currently not satisfactorily treatable with chemotherapeutic protocols. Accordingly, the evaluation of novel agent combinations bears significant potential for identifying novel treatment strategies. In this study, we combined FX-9 with the currently approved therapeutic agents doxorubicin, carboplatin, the demethylating substance azacitidine as well as further potentially antitumorigenic agents such as dichloroacetic acid (DCA) in order to evaluate the respective synergistic potential. The combinations with 1–5 μM FX-9 were evaluated regarding the effect after 72 hours on cell viability, cell count and apoptotic/necrotic cells in two human prostate cancer cell lines (LNCaP, PC-3) and a canine prostate cancer cell line (Adcarc1258) representing androgen-dependent and -independent PC/cPC forms. FX-9 in combination with azacitidine decreases cell viability and increases cell death with positive Bliss values. Furthermore, this decreases the cell count with neutral Bliss values on PC-3. Carboplatin in combination with FX-9 reduces cell viability with a neutral Bliss value and increases cell death on LNCaP with calculated positive Bliss values. DCA or doxorubicin in combination with FX-9 do not show synergistic or additive effects on the cell viability. Based on these results, azacitidine or carboplatin in combination with FX-9 offers synergistic/additive efficacy against prostate adenocarcinoma cell lines in vitro. The beneficial effects of both combinations are worth further investigation.

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Development of 3-aryl-1-isoquinolinamines as potent antitumor agents based on CoMFA

Cited by 21 publications

References 14 publications

Isoquinolinamine FX-9 Exhibits Anti-Mitotic Activity in Human and Canine Prostate Carcinoma Cell Lines

Isoquinolinamine FX-9 Exhibits Anti-Mitotic Activity in Human and Canine Prostate Carcinoma Cell Lines

Regioselective Access to 3-Aryl-1-aminoisoquinolines via Nickel(I)-Catalyzed C–C and C–N Cascade Coupling Reactions from the Substituted 2-(Cyanomethyl)benzonitriles

Evaluation of combination protocols of the chemotherapeutic agent FX-9 with azacitidine, dichloroacetic acid, doxorubicin or carboplatin on prostate carcinoma cell lines

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