Phytosphingosine derivatives with antitumor activity

Details Phytosphingosine derivatives with antitumor activity Phytosphingosine derivatives with antitumor activity

2001-09-07

2003-03-25

Kumar, Shailendra (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S503000, C564S293000, C564S292000, C564S291000

Reexamination Certificate

active

06538032

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an antitumor agent containing a phytosphingosine derivative, and more specifically, to an antitumor agent containing a phytosphingosine derivative of formula I as an active ingredient,
wherein R
1
, R
2
and R
3
respectively represents a hydrogen atom or a C
1
-C
8
alkyl group; and X represents an atom or an atomic group containing a halogen atom, a hydroxyl group, an alkyl sulfonate group or an aryl sulfonate group.
BACKGROUND OF THE INVENTION
Lipids that form a cell membrane generally consist of phospholipid, glycolipid and sphingolipid. These lipids are amphipathic substances and they spontaneously generate completely closed vesicles similar to a cell membrane called ‘liposomes’ upon dispersion in water.
Liposomes can be prepared by using one kind or combining a few of lipids mentioned in the above. Liposomes are known as a good carrier in a drug delivery system. When pharmaceutical agents are incorporated in the liposomes, the hydrophilic portion of a drug is encapsulated into the internal aqueous phase of the liposomes while the hydrophobic portion of a drug is inserted in bilayer of liposomes. As a drug carrier, liposomes can perform accurate delivery of a desired drug in the diseased part and even small amount of drug can be delivered by liposomes. Therefore, liposomes can seriously reduce side effects such as multi-drug resistance in a heavy dosage of drugs. The applications of liposomes as a drug carrier have been expanded recently to cover a variety of fields such as antigens, genes, pharmaceutical drugs including Doxorubicin (an antitumor agent), Amphotericin B (an antifungal agent), other chemical drugs and also a cosmetic field (M. Grunaug et al.,
Eur. J. Med. Res.
21, 13-19, 1998; D. S. Alberts abd D. J. Garcia,
Drugs,
54, 30-35, 1997; F. Braun, et al.,
Transplant Proc.
30, 1481-1483, 1998; V. Heinemann et al.,
Antimicrob. Agents Chemother.
41, 1275-1280, 1997; N. Weiner et al.,
J. Drug Target,
2, 405-410, 1994).
Sphingoid bases are present in humans as phytosphingosin (PhytoS), sphingosine (SPN) and sphinganine, which are amino alcohols having 18 carbon atoms, respectively. These compounds have several stereocenters and D-erythro arrangement at position 3 is discovered in nature. SPN and sphinganine are found in all the tissues of human body while PhytoS is present only in horny layer of human skin. Extensive studies on SPN and its derivatives were initiated at early 1990s and the studies were expedited as these were found to be powerful inhibitors of PKC (protein kinase C). Moreover, the SPN and its derivatives were found to be involved in numerous cellular activities even at low concentration (D. J. Bibel et al.,
Clin. Exper. Dermatol.,
20, 395-400, 1995; D. J. Bibel,
J. Invest. Dermatol.,
98, 269-273, 1992; Y. A. Hannun,
Science,
274, 1855-1859, 1996). These activities being exhibited mostly in horny layer, the interest on the PhytoS has been much increased, however, they are very expensive and also not much had been known about the methods to synthesize their derivatives and their biological activities. In particular, N,N-dimethyl sphingosine (DMS) and N,N,N-trimethyl sphingosinium halide (hereinafter referred to as TMS.hal), derivatives of SPN, are known to be superior to SPN with respect to their inhibitory activities against PKC and are also known to inhibit the growth of various cancer cells both in vivo and in vitro. In addition, it was also revealed that TMS.hal has an antitumor activity and an anti-metastatic activity in murine B16/BL6 melanoma cell line which utilizes liposomal TMS, wherein the mole ratio of egg phosphatidylcholine (egg PC): cholesterol (Chol): TMS.hal is 4.5:4.5:1. However, there is required a relatively large amount of TMS.hal (e.g., about 0.1-0.3 mg/mouse) to exhibit the above-mentioned effects and this often results in side effects such as hemolysis, hemoglobinuria and an inflammatory response. The efforts to resolve these toxicities were carried out by using liposome technology and the results indicated that liposomal TMS.hal was shown non-toxic and was also more effective in in vivo system in inhibiting the growth of cancer cells as well as metastasis as compared to the TMS.hal without liposomes utilization (Y. S. Park, S. Hakomori, S. Kawa, F. Ruan, and Y. Igarashi,
Cancer Res.,
54, 2213-2217, 1994).
There has been a report on phytoS, whose structure is very similar to that of SPN, that reveals the difference in efficiency of DNA transfection in in vitro systems of KK-1, COS-7 and MSC-1 cells due to the difference in the formulation of a helper lipid (T. Paukku et al.,
Chem. Phys. Lipids,
87, 23-29, 1997). The phytoS is also known to have an excellent anti-microbial activity for a wide range of microbes and can alleviate skin irritations by secreting interleukin as a PKC inhibitor. N,N,N-trimethyl phytosphingosinium halide (TMP.hal), a derivative of phytoS, was recently published (Korean Unexamined Patent No. 1999-78610), wherein the derivative is described as a cosmetic component with its use limited to skin protection. Nevertheless, there has been no prior example showing that TMP.hal is an antitumor agent.
SUMMARY OF THE INVENTION
The inventors of the present invention manufactured liposomes that contain a derivative of phytosphingosine of the above formula I in various compositions and confirmed their antitumor activity as well as the anti-metastatic activity. Therefore, the object of the present invention is to provide a phytosphingosine derivative of formula I having an antitumor activity and also to provide antitumor agents comprising the phytosphingosine derivative.


REFERENCES:
patent: 6031135 (2000-02-01), Ruan et al.
patent: 2794366 (2000-12-01), None
patent: 1999-0078610 (1999-11-01), None
Dahiya et al, Cancer Research, vol. 47, p 1031-1035, 1987.*
Alberts, D. S. et al., “Safety Aspects of Pegylated Liposomal Doxorubicin in Patients with Cancer”, Drugs 1997, 54 Suppl. 4, pp. 30-35, (1997).
Grunaug, M. et al., “Liposomal Doxorubicin in Pulmonary Kapsi's Sarcoma: Improved Survival as Compared to Patients without Liposomal Doxorubicin”, Eur J Med Res., vol. 3, pp. 13-19, (1998).
Park, S. Y., “Synthesis of Phytosphingosine Derivatives for Efficient Cationic Liposome-Based DNA-Transfection System” (Part I) and “A Study for Conversion from Penicillin G to L-Penicillamine” (Part II), Masters Thesis, Seoul Women's University, Graduate School, Dept. of Chemistry, 2001.
Paukku, T. et al., “Novel Cationic Liposomes for DNA-Transfection with High Efficiency and Low Toxicity”, CPL, 87 pp. 23-29, (1997).
Park, Y. S. et al., “Liposomal N,N,N-Trimethylsphingosine (TMS) as an Inhibitor of B16 Melanoma Cell Growth and Metastasis with Reduced Toxicity and Enhanced Drug Efficacy Compared to Free TMS: Cell Membrane Signaling as a Target in Cancer Therapy III1”, Cancer Research 54, pp. 2213-2217, (1994).
Hannun, Y. A., “Functions of Ceramide in Coordinating Cellular Responses to Stress”, Science vol. 274, pp. 1855-1859, (1996).
Bibel, D. J. et al., “Antimicrobial Activity of Sphingosines”, Journal of Investigative Dermatology, vol. 98, No. pp. 273, (1992).
Bibel, D. J. et al., “Topical Shingolipids in Antisepsis and Antifungal Therapy”, Clinical and Experimental Dermatology, 20, pp. 395-400, (1995).
Weiner, N. et al., “Liposomes: A Novel Topical Delivery System for Pharmaceutical and Cosmetic Applications”, Journal of Drug Targeting, vol. 2, pp. 405-410, (1994).
Heinemann, V. et al., “Pharmacokinetics of Liposomal Amphotericin B (AmBisome) in Critically III Patients”, Antimicrobial Agents and Chemotherapy, pp. 1275-1280, (1997).
Braun, F. et al., “Is Liposomal Amphotericin B (Ambisome) an Effective Prophylaxis of Mycotic Infections after Liver Transplantation?”, Transplantation Proceedings, 30, pp. 1481-1483 (1998).

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