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Novel multidrug resistance reversal agents.
D Berger1, R Citarella, M Dutia
1Oncology/Immunology/Inflammatory Diseases and Chemical Sciences Sections, Wyeth-Ayerst Research, Pearl River, New York 10965, USA.
Journal of Medicinal Chemistry
|June 23, 1999
Summary
New tetrahydroisoquinoline and isoindoline derivatives effectively reverse multidrug resistance (MDR) in cancer cells. These novel MDR reversal agents show potent in vitro and in vivo activity, offering potential new cancer treatment strategies.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cancer Research
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy, limiting the efficacy of various anticancer drugs.
- P-glycoprotein (P-gp) is a key efflux pump responsible for mediating MDR by expelling drugs from cancer cells.
- Verapamil (VRP), a calcium channel antagonist, has shown some MDR modulating activity but often lacks sufficient potency and specificity.
Purpose of the Study:
- To synthesize and evaluate a novel series of alpha-aryl-alpha-thioether-alkyl, -alkanenitrile, and -alkanecarboxylic acid methyl ester tetrahydroisoquinoline and isoindoline derivatives as potential MDR reversal agents.
- To assess the in vitro cytotoxicity and MDR reversal efficacy of these compounds against human colon carcinoma cells resistant to bisantrene.
- To investigate the in vivo efficacy of promising candidates against drug-resistant cancer models, including vincristine-resistant murine P388 leukemia and human epidermoid carcinoma KB/8.5.
Main Methods:
- Synthesis of 59 novel tetrahydroisoquinoline and isoindoline derivatives (compounds 15a-48).
- In vitro evaluation of cytotoxicity and MDR reversal activity using S1-B1-20 human colon carcinoma cells and bisantrene.
- In vivo assessment of efficacy in vincristine-resistant P388 leukemia and doxorubicin-resistant KB/8.5 xenograft models in mice.
Main Results:
- The majority of synthesized compounds demonstrated superior in vitro MDR reversal activity compared to verapamil (VRP).
- Potent in vitro activity (IC50 < 0.5 microM) was observed for several isoindoline and tetrahydroisoquinoline derivatives, notably compounds 44, 46, 47, and 15m.
- Compounds 15h and 39a, specifically alpha-aryl-alpha-thiotolylalkanenitrile tetrahydroisoquinoline derivatives with alkoxy substituents, exhibited significant in vivo efficacy in both resistant leukemia and solid tumor models with low toxicity.
Conclusions:
- The novel series of tetrahydroisoquinoline and isoindoline derivatives are effective MDR reversal agents, outperforming verapamil in vitro.
- Compounds 15h and 39a show significant promise as potent and low-toxicity MDR modulators for in vivo cancer treatment.
- The mechanism of action is proposed to involve the inhibition of the P-glycoprotein (P-gp) drug efflux pump.