Design and Synthesis of Novel Podophyllotoxins Hybrids and the Effects of Different Functional Groups on Cytotoxicity

Abstract

Development of novel anticancer therapeutic candidates is one of the key challenges in medicinal chemistry. Podophyllotoxin and its derivatives, as a potent cytotoxic agent, have been at the center of extensive chemical amendment and pharmacological investigation. Herein, a new series of podophyllotoxin-N-sulfonyl amidine hybrids (4a–4v, 5a–5f) were synthesized by a CuAAC/ring-opening procedure. All the synthesized podophyllotoxins derivatives were evaluated for in vitro cytotoxic activity against a panel of human lung (A-549) cancer cell lines. Different substituents’, or functional groups’ antiproliferative activities were discussed. The –CF3 group performed best (IC50: 1.65 μM) and exhibited more potent activity than etoposide. Furthermore, molecular docking and dynamics studies were also conducted for active compounds and the results were in good agreement with the observed IC50 values.

Chemistry and Biology of Podophyllotoxins: An Update

“…[48] Against lung cancer cells A-549, compound 137 c showed the optimal activity with an IC 50 value of 1.65 μM. [49] As described in Scheme 14, Vishnuvardhan et al used click chemistry to synthesize PPT derivatives with 1,2,3-triazole heterocycles (139 a-139 l). Against cervica cancer Hela cells, compounds139c and 139 j were more active than the anticancer drug etoposide (IC 50 = 2.24 μM) with IC 50 values of 0.9 and 0.07 μM, respectively.…”

“…Interestingly, when the above Scheme 13. Synthesis of compounds 135 a,b, 136 a-136 v and 137 a-137 f. [47,49] reaction occurred in acetonitrile solution, 4-epipodophyllotoxin (57) was obtained. Then compounds 57 and 127 were esterified with biotin to produce 152 a,b.…”

“…A series of PPT‐ N ‐sulfonyl amidine derivatives ( 136(a–v) and 137(a–f) ) were also obtained by the copper‐catalyzed sulfonyl azide–alkyne multicomponent reaction with the amino derivatives 134 a,b [48] . Against lung cancer cells A‐549, compound 137 c showed the optimal activity with an IC 50 value of 1.65 μM [49] …”

“…Scheme 13. Synthesis of compounds 135 a,b, 136 a-136 v and 137 a-137 f [47,49]. a. MeSO 3 H, NaI, DCM, then, H 2 O-Acetone, BaCO 3 , rt.…”

Phytochemicals as Chemo-Preventive Agents and Signaling Molecule Modulators: Current Role in Cancer Therapeutics and Inflammation

“…In a study, independent of the insulin-like growth factor-1 receptor (IGF-1R) pathway, it interfered with microtubule dynamics to decrease cancer. There is no evidence of neurotoxicity with PPP, and the only adverse effect is neutropenia, which may be reversed [ 201 , 202 , 203 , 204 ].…”