Cyanine-containing compounds for cancer imaging and treatment

a technology of cyanine-containing compounds and cancer imaging, which is applied in the field of cyanine-containing compounds for cancer imaging and treatment, can solve the problems that most cyanine dyes are not effective for in vitro treatment or imaging, and achieve the effect of improving the quality of life and improving the effect of imaging

Inactive Publication Date: 2015-07-02
EMORY UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0019]Compounds of the invention are useful in various surgical and medical procedures, as will be appreciated by one having ordinary skill in the art. For example, during active surgery, surgeons can use the methods of the invention to identify which lymph node may contain tumors and which area may have disseminated tumor cells. The current practice is taking a frozen section and a step section of the suspected areas by pathologists. The methods of the invention provide real-time results.

Problems solved by technology

However, most cyanine dyes are not effective for in vitro treatment or imaging because the dyes are toxic to normal cells as well as tumor cells, or are poorly soluble in pharmaceutically acceptable solvents.

Method used

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  • Cyanine-containing compounds for cancer imaging and treatment
  • Cyanine-containing compounds for cancer imaging and treatment
  • Cyanine-containing compounds for cancer imaging and treatment

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0069]The synthesis of compound 8 is shown in Scheme 1.

[0070]Benz[c,d]indole-2(1H)-thione (2). This compound was obtained in an 93% yield; mp 146-148° C.; (reported: yield 82%, mp 156 dec).2,3

[0071]2-Methylthiobenz[c,d]indole hydroiodide (3). This compound was prepared by using the reported procedures.2,4 Since the product was unstable, it used in the next step without further purification.

[0072]2-(2,2-Dimethyl-4,6-dioxo-1,3-dioxane-5-yliden)1Hbenz[c,d]indole (4). This compound was obtained in an 85% yield; mp 220° C. (dec.); (reported: yield 94%, mp 223° C.).1,2

[0073]Ethyl 2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-1H-benz[c,d]indole-1-hexanoate (5). A mixture of compound 4 (3 g, 10.2 mmol), ethyl 6-bromohexanoate (5.5 g, 30.6 mmol) and K2CO3 (4.2 g, 30.60 mmol) were heated in DMF (40 mL) at 90° C. for 18 hr under a nitrogen.atmosphere. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on s...

example 2

Preparation of MHI-148 (compound 10)

[0076]As shown in Scheme 2, a solution of salt 9 (1.00 g, 2.82 mmol), Vilsmeier-Haack reagent 75 (507 mg, 1.4 mmol) and anhydrous sodium acetate (925 mg, 11.28 mmol) in acetic anhydride (30 mL) was heated to 70° C. for 1 h under a nitrogen atmosphere. The reaction progress was monitored by Vis / NIR spectroscopy. The green solution was cooled to room temperature, then poured into saturated solution of sodium iodide. The crude product was filtered off, washed with ether and recrystallized from methanol / ether providing 0.8 g (1.0 mmol, 71%); 1H NMR, δ 1.42 (m, 6H), 1.57 (m, 6H), 1.75 (m, 4H), 2.19-2.21 (m, 6H), 2.84 (m, 2H), 4.26 (m, 2H) 6.30-6.37 (m, 2H), 7.28-7.32 (m, 4H), 7.40-7.51 (m, 4H), 7.64 (m, 2H), 8.28 (d, J=8.3 Hz, 2H), ESI-MS m / z 742 ([M+], 100); ESI-HRMS calcd for C42H52N2O4Cl (Mt CH3COO−) 683.3616. Found 683.3608. λmax Abs=780 nm and λmax FL=800 nm.

[0077]Synthesis of cyclopentene ring-containing structures can be carried out using method...

example 3

Evaluation of Organic Cyanine-Containing Compounds as Imaging Agents

[0078]FIG. 1 shows imaging of human cancer cells including prostate (LNCaP, ARCaPE, ARCaPM, C4-2, PC-3), liver (HepG2), osteosarcoma (MG63), breast (MCF-7), kidney (RCC), bladder (T-24), cervical (HeLa), leukemia (K562) and lung (H358) with MHI-148. Cancer cells show a significant uptake of MHI-148 (dark color), while corresponding normal human or mouse cells (e.g. normal prostate fibroblasts, NPE; marrow stromal cells, BMC; normal vascular endothelial cells, VEC; or mouse macrophage RAW cells) failed to yield any time- or concentration-dependent uptake of MHI-148 in culture. Normal epithelial cells (e.g. normal prostate epithelial cells, NPE and normal human skin epithelial cells, HaCaT) showed a low uptake of MHI-148. All the cells were cultured with 100 μM MHI-148 in basal media (T-medium with 5% fetal bovine serum and 1% antibiotics) for two hours and were imaged under an inverted microscope. These conditions ar...

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Abstract

This invention relates generally to cyanine-containing compounds; pharmaceutical compositions comprising cyanine-containing compounds; and methods of using cyanine-containing compounds for cancer cell imaging, cancer cell growth inhibition, and detecting cancer cells, for example. Compounds of the invention are preferentially taken up by cancer cells as compared to normal cells. This allows many uses in the cancer treatment, diagnosis, tracking and imaging fields.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application takes priority from U.S. provisional application Ser. No. 60 / 959,413, filed Jul. 13, 2007, the disclosure of which is hereby incorporated by reference to the extent not inconsistent with the disclosure herein.BACKGROUND OF THE INVENTION[0002]Dyes that absorb and emit light in different regions of the electromagnetic spectrum are currently used for various biomedical applications. Optical imaging in the near infrared region (“NIR”) (680-1600 nm) has received much attention due to the low intrinsic absorption of biomolecules in that region and the penetration of NIR light several centimeters into tissue, a depth sufficient to image most small animal models (see, for example, Rao, et al., Current Opinion in Biotechnology, 2007, 18:17-25). “Windows” for imaging biomolecules are known where various biological molecules (such as oxyhemoglobin, deoxyhemoglobin, lipids, and water) have limited interference. The NIR wavelengths of...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D209/10
CPCC07D209/10C07D209/60C07D209/92A61K31/404A61P35/00A61K49/00G01N33/5008
Inventor CHUNG, LELAND W.K.STREKOWSKI, LUCJANSHI, CHUNMENGHENARY, MAGEDPATONAY, GABORKRUTAK, JAMES J.YANG, XIAOJIANZHU, GUODONGWANG, RUOXIANGZHAU, HAIYEN E.
Owner EMORY UNIVERSITY
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