The present invention, in some embodiments thereof, relates to novel compounds and, more particularly, but not exclusively, to derivatives of nucleoside analogs which can be used in anti-cancer therapy.
Oncogenic viruses are estimated to be involved in about 16% of neoplasia. They are estimated to be involved in 10% of cases in high-income countries to 25% in Africa. However, there are some cancer types for which a viral origin is suspected, although not yet conclusively proven, therefore it is likely that these percentages are underestimates.
Epidemiological and molecular data support the notion that viruses are involved in processes of cell transformation and oncogenesis. The mechanism proposed for tumorigenesis by SV40 is related to viral oncoproteins, the large T antigen (Tag) and the small t antigen (tag). Tag acts mainly by blocking the functions of p53 and RB tumor suppressor proteins, as well as by inducing chromosomal aberrations in the host cell. These chromosome alterations may hit genes which play an important role in oncogenesis and generate genetic instability in tumor cells. The chromosome damage in the infected cells may explain the low viral load in SV40-positive human tumors and the observation that Tag is expressed only in a fraction of tumor cells. “Hit and run” seems the most plausible mechanism to explain this situation. Some supporting evidence for the implication of viruses in prostate carcinoma show prevalence of polyomaviruses in 19% of prostate cancer cases. Moreover, individuals harboring mutations or variants that impair function of ribonuclease L, known to play a role in defense against viral infection, were found to be susceptible to prostate cancer and a survey of 86 tumors by specific RT-PCR detected the virus in 40% of these patients.
Nucleoside analogs have been used for anti-viral therapy. For example, acyclovir and ganciclovir (see, Scheme 1 below) have been the mainstream therapy for infections by herpes viruses (e.g. herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EPV) and cytomegalovirus (CMV)). These deoxyguanosine analogs are compounds that must be phosphorylated first by the viral thymidine kinase (V-TK) and then by cellular kinases to their triphosphate active form [Brigden & Whiteman, 1983]. These analogs exert their antiviral activity by inhibiting the viral DNA polymerase (pol) and terminating viral DNA synthesis.

Because acyclovir and ganciclovir are poor substrates for human monophosphatase kinase they have high selectivity and few side-effects, e.g., acyclovir has a selective activity which results in the inhibition of herpes virus replication at concentrations 300-3000-fold lower than those inhibiting mammalian cellular functions [Brigden & Whiteman, 1983]. Ganciclovir is a derivative of acyclovir with the addition of a hydroxymethylene, at the 3′ carbon acyclic side-chain which gives increased activity, especially against HSV. Additional, other purinic and pyrimidinic antiviral agents with improved activity and oral bioavailability have been described [De Clerq & Field, 2006].
While due to the selectivity of these deoxyguanosine analogs these compounds are highly safe for humans, this selectivity renders these compounds lacking an anticancer activity per se.
However, these anti-viral nucleoside analogs may have an anticancer activity when combined with other compounds. Such combinations are being investigated for use in cancer therapy according to two approaches: suicide gene therapy and combination therapy of acyclovir with a histone deacetylase (HDAC) inhibitor.
Gene therapy strategy is based on the transfection of cancer cells with viral TK (V-TK) followed by treatment with prodrugs such as acyclovir or ganciclovir, as described by Dachs et al., 2005. In this gene-directed enzyme prodrug therapy (GDEPT), the gene encoding the enzyme is delivered to tumor cells, followed by administration of ganciclovir, which is phosphorylated by V-TK to the monophosphate, which then undergoes a series of intracellular reactions resulting in the formation of the corresponding triphosphate. This triphosphate competes with deoxyguanosine triphosphate in DNA elongation during cell division, resulting in inhibition of DNA polymerase and single-strand breaks. The combination of enzyme and prodrug has specificity for rapidly dividing tumor cells invading normal quiescent tissue resulting in selective tumor cell-killing activity.
The second strategy focuses on lymphoproliferative disorders associated with Epstein-Barr virus (EBV) infections. Lymphoproliferative diseases associated with the EBV occur in immunocompromised patients as well as in other types of neoplasm e.g., oral and gastric cancer [Herrmann & Niedobitek, 2003; Perrine et al., 2007].
The lack of viral TK expression in EBV-positive tumors is caused by viral latency, which makes antiviral therapy alone ineffective as an antineoplastic therapy. The combination treatment strategy is based on using pharmacological induction of the latent viral TK gene and enzyme in tumor cells with a histone deacetylase (HDAC) inhibitor along with administration of ganciclovir. This treatment was developed as a combination of arginine butyrate and ganciclovir that was reported to be reasonably well-tolerated and seemed to have significant biological activity in vivo in EBV(+) lymphoid malignancies which are refractory to other regimens [Perrine et al., 2007].
U.S. Pat. No. 4,146,715 teaches purine derivatives, including amides and esters, as well as uses thereof as antiviral agents or in the preparation of antiviral agents.
WO 05/120577 teaches conjugates of a chemotherapeutic agent which are capable of releasing formaldehyde upon cleavage, and uses thereof.
USPTO Backgrounds
USPTO Backgrounds