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MCAT

Unit 3: Lesson 1

Chemical and physical sciences practice passage questions

Synthesis of anti-tumor drug Combretastatin and its derivatives

Problem

Combretastatin A-4 (start text, C, A, negative, end text, 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.
start text, C, A, negative, end text, 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, start text, C, A, negative, end text, 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, start text, C, A, negative, end text, 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 start text, C, A, negative, end text, 4 derivatives. The synthetic route is depicted below:
Figure 1. Synthesis of Combretastatin A-4 (start text, C, A, negative, end text, 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. start superscript, 1, end superscript, start text, H, negative, N, M, R, end text spectrum of start text, C, A, negative, end text, 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.
Which of the Combretastatin A-4 derivatives (Compounds 5-9) is represented by the start superscript, 1, end superscript, start text, H, negative, N, M, R, end text spectrum above in Figure 3?
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