Organic chemistry: Synthesis of anti-tumor drug derivatives and NMR analysis

Combretastatin A-4 ($\text{CA-}4$‍) was first extracted from the tree combretum caffrum and has proven to be a potent anti-tumor drug. It shares most of its biosynthetic pathway with colchicine, as well as the capacity to inhibit tubulin polymerization. Colchicine inhibits microtubule polymerization by binding to the β-subunit of tubulin. While cancer cells are significantly more vulnerable to colchicine poisoning than normal cells, the overall cytotoxicity makes the therapeutic value of colchicine very limited.

$\text{CA-}4$‍ is one of the first promising agents shown to have both anti-tumor and anti-vascular properties. By binding to a site different from the colchicine site, $\text{CA-}4$‍ not only inhibits microtubule assembly but also causes drastic shape change in endothelial cells. By exploiting the differences between tumor and normal tissue endothelium, $\text{CA-}4$‍ is able to block pre-existing blood vessels and cause extensive cell death in the tumor core. In hopes of finding a novel derivative with greater bioactivity, a research group decides to undergo the design and synthesis of several $\text{CA-}4$‍ derivatives. The synthetic route is depicted below:

Figure 1. Synthesis of Combretastatin A-4 ($\text{CA-}4$‍) and derivatives through Perkins Condensation

An alternative route for synthesis is the Wittig reaction, which is a reaction between an aldehyde or ketone with a triphenyl phosphonium ylide (Wittig reagent) to give an alkene and triphenylphosphine oxide:

Figure 2. Wittig Reaction

During the course of the experiment, one of the collection fractions was mislabeled, and the research assistant performed spectral analysis to determine the identity of the sample.

Figure 3. ${}^1\text{H-NMR}$‍ spectrum of $\text{CA-}4$‍ derivative in mislabeled sample

Source: Adapted from a paper by M. Ma, et al. Copyright 2013 by Ma et al.; licensee Chemistry Central Ltd.