Malignant tumor is one of the common diseases that threaten human health, and ranks first among all diseases in terms of mortality rate. Regarding anti-tumor drugs available in current clinical application, their toxicity is a prominent problem in tumor chemotherapy. Improving the effectiveness of tumor treatment and simultaneously reducing drug toxicity are the key study subjects on current cancer drugs.
Cytidine derivatives having anti-tumor effects includes cytarabine and gemcitabine. Cytarabine is turned into active triphosphate cytarabine in the body to achieve anti-cancer effect. Triphosphate cytarabine prevents DNA synthesis and inhibits cell growth by inhibiting NDA polymerase and inserting a small amount of DNA, which is mainly used for the treatment of acute myeloblastic leukemia. However, cytarabine has comparatively great toxic side-effects, which may cause bone marrow suppression, white blood cell reduction and thrombocytopenia to the hematopoietic system. Aplastic anemia or megaloblastic anemia may occur in severe cases. Hyperuricemia may occur for the patient with leukemia or lymphoma inearly treatment, and uric acid nephropathy may occur in severe cases.
Gemcitabine is a derivative of deoxycytidine, and is similar to cytarabine in structure and metabolism. Gemcitabine is, through nucleoside monophosphate kinase in the cell, catalyzed into activated Dipridecyl diphosphate (dFdCDP) and Tripolytic acid triphosphate (dFdCTP), and dFdCTP impedes DNA synthesis through inhibiting DNA polymerase. The DNA chain discontinues to extend clue to the incorporation to DNA, thereby inhibiting the growth of tumor cells.
Gemcitabine is applicable for pancreatic cancer (primary and secondary treatments), non-small cell lung cancer, breast cancer, ovarian cancer, and head and neck squamous cell carcinoma. However, the toxicity of gemcitabine is also relatively great. Its adverse reactions are bone marrow suppression, such as leucopenia, thrombocytopenia and anemia; gastrointestinal reactions such as mild nausea, vomiting and abnormal liver function; fever, flu-like symptoms, fatigue, mucositis and so on.
After the above-mentioned cytidine derivatives enter the human body, the tumor cells will produce multi-drug resistance gene. Besides, the amino on the ring are easily acetylated, causing loss of compound anticancer activity and other resistance factors. The above-mentioned cytidine derivatives have great toxic side-effects, and tend to produce drug resistance.
In order to reduce the toxicity of cytarabine and gemcitabine, and improve or maintain anti-tumor efficacy, researchers modify the chemical structure of cytidine derivatives.
For example, Synthesis and Biological Activity of a Gemcitabine Phosphoramidate Prodrug (J. Med. Chem 2007, 50, 3743-3746; Weidong Wu) reported a kind of gemcitabine phosphate prodrug.
U.S. Pat. No. 7,265,096 B2 (application Ser. No. 10/701,965) disclosed gemcitabine prodrugs, pharmaceutical compositions and uses thereof. This article substituted the amino of gemcitabine, hydrogen atom of hydroxyl and hydrogen atom of hydroxymethyl on ribofuranose. The hydrogen atom of hydroxymethyl on the ribofuranose was substituted by H, acyl, substituent acyl, acyloxy-carbonyl, substituent acyloxy-carbonyl, oxy-carbonyl and substituent oxy-carbonyl; the hydrogen atom of hydroxyl on the ribofuranose was substituted by H, acyl, substituent acyl, acyloxy-carbonyl, substituent acyloxy-carbonyl, oxy-carbonyl and substituent oxy-carbonyl; the amino was substituted by —N═C(R10)(R11) or —NHR12, wherein, R12 was C5-C9 acyl or C5-C9 substituent acyl. The compound prepared by this patent is a prodrug that only exhibits anti-tumor activity after transformation in the body. In addition, clinical studies discover that gemcitabine prodrug has high toxicity and low anti-tumor activity, which is not yet developed as a medicine.