Anti-Tumor Effects Of Structurally Simplified Ecteinascidins Analogues

Ecteinascidins (ETs) are a series of marine original products which are tetrahydroisoquinoline alkaloids and form DNA-adducts through covalent binding to DNA. They exhibit potent anti-cancer activity and unique tumor selectivity. ET-743is one of the most evaluated drugs and was authorized for the treatment of soft tissue sarcoma and ovarian cancer by the European Commission. Although extremely expensive as a marketing drug, clinical use of ET-743is still restricted by the shortage of supply as a result of scarcity in natural resources and inefficient synthesis due to its complicated structure. It is reasonable to discover simplified ETs analogues as alternative agents to overcome this obstacle. GJ7-1and GJ7-2are two new chemicals synthesized during the effort to optimize the structures of existing simplified ETs analogues. However both compounds possess lower antineoplastic activity that is two orders of magnitude less than antineoplastic activity compared with ET-743although they are similar in structures. The pharmacological effects and DNA targeting of these two novel compounds were investigated to decipher their decreased cytotoxicity.Both GJ7-1and GJ7-2exerted anti-proliferation effect on15tumor cell lines with IC50at sub-micromolar level, without obvious tumor type selectivity. However in transplantable mouse EHS sarcoma model, GJ7-2(20mg/kg and40mg/kg) had little effect on tumor growth.The two compounds had no effect on DNA electrophoretic mobility shift and they did not compete for fluorescent probe binding to DNA either in intercalating mode or in minor groove binding mode. They induced a change in cell cycle distribution of A549cells, but with less dramatic blockage of G2/M phase. Both of the compounds did not induce a significant apoptosis in A549cells probed by either Hochest33342staining or Annexin V/PI staining.The compounds inhibited the heat induced expression of HSP70without affecting the basal level in A549cells. Although ET-743was reported to inhibit the expression of induced HSP70which through binding to DNA and inhibiting transcription process of hsp70gene, the inhibition mechanism of GJ7-1or GJ7-2should not be the same to ET-743as they had no interaction with DNA.The two agents showed a disturbance on A549cell microtubule organization only at extremely high concentrations (5μmol/L) after longer incubation (8h) rather than at their corresponding concentrations for cell growth inhibition. Therefore, it may not contribute to their cytotoxicity.In conclusion, this two simplified ETs analogues lost their ability of targeting to DNA, resulting in the decreased anti-tumor activity accompanying the changes or losses of their characteristic pharmacological effects. A change in the functional groups in the chemical structure of these compounds may be responsible for their significant loss of DNA targeting.