Reengineered epipodophyllotoxin

Abstract

A variant structural skeleton of epipodophyllotoxin was synthesized and found to rival the natural cyclolignan in antiproliferative and microtubule destabilizing properties. This discovery leads to a new structural class of tubulin targeting agents.

Figure 1

Structures of podophyllotoxin (1), epipodophyllotoxin (2), etoposide (3) and teniposide (4).

Figure 2

Is systematic interrogation of the chemical space occupied by rings AB and E possible?

Figure 3

Strategy leading to reengineered epipodophyllotoxin 11.

Figure 4

Molecular docking poses (black) of 21 (A) and 11 (B) overlaid with that of 1 (red).

Figure 5

Microtubule organization in HeLa cells during interphase (A–E) and mitosis (F–J). Hela cells were treated for 3 hours with the indicated compounds at their MTT-related GI₅₀ concentrations (see Table). Following drug treatment, cells were probed for microtubules (green), centromeres (red) and DNA (blue). Bar, 10μ.

Scheme 1

Synthesis of Diels-Alder products 18 (exo) and 19 (endo)

Scheme 2

Elaboration of the Diels-Alder products 18 and 19 to reengineered epipodophyllotoxin 11 and its C-3 epimer 24.