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Noscapine analogs and their use in treating cancers, including drug-resistant cancers

a technology of nascapine and its analogs, which is applied in the field of nascapine analogs, can solve the problems of hypersensitivity reactions, limited pharmacological profile of microtubule-binding agents, and limited use of microtubule drugs such as vincas and taxanes

Inactive Publication Date: 2010-09-09
EMORY UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]The noscapine analogues bind tubulin, effectively inhibit cell proliferation of 1A9 (ovarian cancer cells) and its paclitaxel-resistant variant (1A9 / PTX22), and human lymphoblastoid cells CEM, and its vinblastine- (CEM / VLB 100) and teniposide- (CEM / VM-1-5) resistant variants.

Problems solved by technology

Although useful, currently used microtubule drugs such as vincas and taxanes are limited due to the emergence of drug resistance.
The pharmacological profile of microtubule-binding agents, however, has not been ideal.
Most of them need to be infused over long periods of time in the clinic because they are not water-soluble, and can cause hypersensitive reactions due to the vehicle solution (Rowinsky, 1997).
Furthermore, normally dividing cells within the healthy tissues such as intestinal crypts, hair follicles, and the bone marrow are also vulnerable to these agents, leading to toxicities (Rowinsky, 1997).

Method used

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  • Noscapine analogs and their use in treating cancers, including drug-resistant cancers
  • Noscapine analogs and their use in treating cancers, including drug-resistant cancers
  • Noscapine analogs and their use in treating cancers, including drug-resistant cancers

Examples

Experimental program
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Effect test

example 1

Preparation of 9-Nitro-Nos((S)-6,7-dimethoxy-3-((R)-4-methoxy-6-methyl-9-nitro-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one)

[0086]To a solution of noscapine (4.134 g, 10 mmol) in acetonitrile (50 ml), silver nitrate (1.70 g, 10 mmol) and trifluoroacetic anhydride (5 ml, 35 mmol) were added. After one hour of reaction time, the reaction progress was monitored using thin layer chromatography (10% methanol in chloroform) and the reaction mixture was poured into 50 ml of water and extracted with chloroform (3×50 ml). The organic layer was washed with brine, dried over anhydrous MgSO4 and the solvent was evaporated in vacuo. The desired product, (S)-6,7-dimethoxy-3-((R)-4-methoxy-6-methyl-9-nitro-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one (9-nitro-nos) was obtained as yellow crystalline powder by flash chromatography (silica gel, 230-400 mesh) with 10% methanol in chloroform as an eluent. mp 178.2-178.4° C.; IR: 1529, ...

example 2

Evaluation of the Tumulin Binding Properties of 9-Nitro-Nos

[0093]Cell Lines and Chemicals:

[0094]Cell culture reagents were obtained from Mediatech, Cellgro. CEM, a human lymphoblastoid line, and its drug-resistant variants—CEM / VLB100 and CEM / VM-1-5, were provided by Dr. William T. Beck (Cancer Center, University of Illinois at Chicago). CEM-VLB100, a multi-drug resistant line selected against vinblastine is derived from the human lymphoblastoid line, CEM and expresses high levels of 170-kd P-glycoprotein (Beck and Cirtain, 1982). CEM / VM-1-5, resistant to the epipodophyllotoxin, teniposide (VM-26), expresses a much higher amount of MRP protein than CEM cells (Morgan et al., 2000). The 1A9 cell line is a clone of the human ovarian carcinoma cell line, A2780. The paclitaxel-resistant cell line, 1A9 / PTX22, was isolated as an individual clone in a single-step selection, by exposing 1A9 cells to 5 ng / ml paclitaxel in the presence of 5 μg / ml verapamil, a P-glycoprotein antagonist (Giannaka...

example 3

Synthesis of Halogenated Noscapine Analogues

(S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquino-lin-5-yl)-6,7-dimethoxyisobenzofuran-1(3H)-one

[0169]To a flask containing noscapine (20 g, 48.4 mmol) was added minimum amount of 48% hydrobromic acid solution (˜40 ml) to dissolve or make a suspension of the reactant. To the reaction mixture was added freshly prepared bromine water (˜250 ml) drop wise until an orange precipitate appeared. The reaction mixture was then stirred at room temperature for 1 h to attain completion, adjusted to pH 10 using ammonia solution to afford solid precipitate. The solid precipitate was recrystallized with ethanol to afford bromo-substituted noscapine. Yield: 82%; mp 169-170° C.; IR: 2945 (m), 2800 (m), 1759 (s), 1612 (m), 1500 (s), 1443 (s), 1263 (s), 1091 (s), 933 (w) cm−1; 1H NMR (CDCl3, 400 MHz), δ 7.04 (d, 1H, J=7 Hz), 6.32 (d, 1H, J=7 Hz), 6.03 (s, 2H), 5.51 (d, 1H, J=4 Hz), 4.55 (d, 1H, J=4 Hz), 4.10 (s, 3H), 3.98 (...

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Abstract

Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are noscapine analogs. The compounds and compositions can be used to treat and / or prevent a wide variety of cancers, including drug resistant cancers. While the antitussive plant alkaloid, noscapine, binds tubulin, displays anticancer activity, and has a safe pharmacological profile in humans, structure-function analyses pointed to a proton at position 9 of the isoquinoline ring that can be modified without compromising tubulin binding activity. Noscapine analogs with various functional moieties at position 9 on the isoquinoline ring kill human cancer cells resistant to other anti-microtubule agents, such as vincas and taxanes. Representative analogs include the 9-nitro, 9-bromo-, 9-iodo-, and 9-fluoro-noscapines, which bind tubulin and induce apoptosis selectively in tumor cells (ovarian and T-cell lymphoma) resistant to paclitaxel, vinblastine and teniposide. Surprisingly, treatment with one of the analogs, 9-nitro-nos, at doses as high as 100 μM, did not affect the cell cycle profile of normal human fibroblasts. This selectivity for cancer cells represents a unique edge over the other available antimitotics. The compounds can perturb the progression of cell cycle by mitotic arrest, followed by apoptotic cell death associated with increased caspase-3 activation and appearance of TUNEL-positive cells. Thus, the compounds are novel therapeutic agents for a variety of cancers, including ovarian and T-cell lymphoma cancers, even those that have become drug-resistant to currently available chemotherapeutic drugs.

Description

FIELD OF THE INVENTION[0001]The present invention relates to noscapine analogs, pharmaceutical compositions incorporating the noscapine analogs, and methods of using the compounds and compositions to treat cancers, including drug resistant cancers.BACKGROUND OF THE INVENTION[0002]Microtubules are major cytoskeletal structures responsible for maintaining genetic stability during cell division (Sammak and Borisy, 1987; McIntosh, 1994; Desai and Mitchinson, 1997). The dynamics of these polymers is absolutely crucial for this function that can be described as their growth rate at the plus ends, catastrophic shortening, frequency of transition between the two phases, pause between the two phases, their release from the microtubule organizing center and treadmilling (Margolis and Wilson, 1981; Mitchison and Kirschner, 1984; Kirschner and Mitchison, 1986; Margolis and Wilson, 1998; Jordan and Wilson, 2004). Microtubule lattice also serves as tracks for the axonal transport of organelles dr...

Claims

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Application Information

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IPC IPC(8): A61K31/4741C07D491/056A61P35/00A61P35/02
CPCC07D491/056A61K45/06A61K31/4741A61P35/00A61P35/02
Inventor JOSHI, HARISH C.ANEJA, RITUVANGAPANDU, SURYA N.
Owner EMORY UNIVERSITY
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