Borylated porphyrin is one of building blocks in coupling reactions to obtain the multiporphyrin containing two,
three or more subunits of porphyrins. In this study, one of borylated porphyrin derivatives, 5-(4,4,5,5 – tetramethyl
– 1,3,2 – dioxoborolane) -10,20 – diphenylporphyrin (B-DPP) was synthesized through four steps of reactions. The
building block of porphyrin, dipyrromethane was synthesized through a condensation reaction in the presence of
trifluoroacetic acid as catalyst. Subsequently, A2
B2 type of porphyrin was obtained by Lindsey condensation reaction
followed by bromination reaction to produce porphyrin halide. Suzuki cross coupling reaction between porphyrin
halide and pinacolborane with Pd (II) catalyst afforded 40% of borylayed porphyrin. The product was successfully
characterized by using nuclear magnetic resonance spectroscopy (NMR) and UV-Visible spectroscopy (UV-Vis). This
compound crystallized from a mixture of dichloromethane/methanol to give violet needle-like crystal. Crystallographic
studies showed this compound crystallized in monoclinic system with space group of P21
/c.
Development of resistance to chemo- and radiotherapy in patients suffering from advanced cervical cancer narrows the therapeutic window for conventional therapies. Previously we reported that a combination of the selective BCL-2 family inhibitors ABT-263 and A-1210477 decreased cell proliferation in C33A, SiHa and CaSki human cervical cancer cell lines. As ABT-263 binds to both BCL-2 and BCL-XL with high affinity, it was unclear whether the synergism of the drug combination was driven either by singly inhibiting BCL-2 or BCL-XL, or inhibition of both. In this present study, we used the BCL-2 selective inhibitor ABT-199 and the BCL-XL selective inhibitor A1331852 to resolve the individual antitumor activities of ABT-263 into BCL-2 and BCL-XL dependent mechanisms. A-1210477 was substituted for the orally bioavailable S63845. Four cervical cancer cell lines were treated with the selective BCL-2 family inhibitors ABT-199, A1331852 and S63845 alone and in combination using 2-dimensional (2D) and 3-dimensional (3D) cell culture models. The SiHa, C33A and CaSki cell lines were resistant to single agent treatment of all three drugs, suggesting that none of the BCL-2 family of proteins mediate survival of the cells in isolation. HeLa cells were resistant to single agent treatment of ABT-199 and A1331852 but were sensitive to S63845 indicating that they depend on MCL-1 for survival. Co-inhibition of BCL-2 and MCL-1 with ABT-199 and S63845, inhibited cell proliferation of all cancer cell lines, except SiHa. However, the effect of the combination was not as pronounced as combination of A1331852 and S63845. Co-inhibition of BCL-XL and MCL-1 with A1331852 and S63845 significantly inhibited cell proliferation of all four cell lines. Similar data were obtained with 3-dimensional spheroid cell culture models generated from two cervical cancer cell lines in vitro. Treatment with a combination of A1331852 and S63845 resulted in inhibition of growth and invasion of the 3D spheroids. Collectively, our data demonstrate that the combination of MCL-1-selective inhibitors with either selective inhibitors of either BCL-XL or BCL-2 may be potentially useful as treatment strategies for the management of cervical cancer.