Thus, the mechanism of action of CNDAC is distinct from other clinically energetic nucleosides. To obtain oral bioavailability, CNDAC was derivatized with a palmitoyl group at the N4 exocyclic amine this was designated as CS 682 by Sankyo Co. , Ltd. , Tokyo, Japan, the unique pharmaceutical sponsor. The fatty acid side chain on the N4 group of the cytosine moiety improves oral bioavailability and lowers inactivation by deamination.

Subsequently, after Cyclacel Pharmaceuticals, Berkeley Heights, NJ, USA, assumed clinical advancement of the compound in 2003, this was re designated at first as CYC 682, and Issue Xa subsequently as sapacitabine. Hence, all the names indicate the identical chemical entity, but recognize the respective sources of compound. As is the situation with other deoxycytidine analogs, for example, ara C, gemcitabine, reports in cell lines demonstrated that Factot Xa is phosphorylated to the monophosphate by deoxycytidine kinase, albeit with comparatively poor effectiveness compared with dCyd or the other analogs. Cells lacking this enzyme were drastically resistant to the analog. Also, CNDAC is a substrate for deamination by cytidine deaminase, which generates the inactive uracil derivative CNDAU. The triphosphate accumulates in a concentration dependent manner, and competes with dCTP for incorporation into DNA.

CNDAC was demonstrated to have strong antitumor activity in preclinical research. The antiproliferative results of CNDAC in terms of IC50 values have been more potent than people observed with ara C. The analog showed broad spectrum activity against tumor cell lines and also in the P388 leukemia mouse model. CNDAC was more successful than cytarabine in some human tumor cell lines derived from lung, abdomen and osteosarcoma and showed excellent activity against tumor cell lines refractory to cytarabine. However, the orally administered prodrug was much more potent against human tumor xenografts than CNDAC or 5 fluorouracil. It was also efficient against several human organ tumor xenografts more than a wider dose assortment and with fewer toxicities.

CS 682 was also efficient against P388 human leukemia cells resistant to a assortment of other agents including mitomycin C, vincristine, 5 fluorouracil and cisplatin in syngeneic mice. Employing highresolution magnetic imaging, fluorescent peptides Wu et al. demonstrated that CS 682 delayed the development of orthotopically implanted AX3488 liver tumors, and also delayed their meta static behavior. The metastatic behavior of an orthotopic model of pancreatic carcinoma was delayed, and general survival of the mice was prolonged by CS 682. A liposomal formulation of CNDAC showed activity against Meth A sarcoma bearing mice when injected intravenously. The antitumor activity of the liposomally encapsulated formulation was much more potent than that of the parent drug large-scale peptide synthesis suggesting that the liposomal planning enhanced therapeutic efficacy whilst at the exact same time decreasing toxicity.

Sapacitabine in blend with histone deacetylase inhibitors induced an enhance in apoptosis and demonstrated substantial benefit compared with the single agent treatments both in vitro and in xenografts of the MV4 11 myeloid leukemia. The encouraging actions in preclinical designs offered rationale for clinical trials of the bioavailable prodrug formulation. Two multicenter Phase I clinical trials of CS 682 in patients with advanced solid tumors have been reported. Two schedules of oral administration were investigated, once day-to-day for 5 days for 4 weeks and after daily on days 1, 3 and 5 for 4 weeks. In the former trial, the drug was investigated in 47 individuals with twelve doses that ranged amongst 1.