Issue Date: February 4, 2008
The Surprise That Wasn't
I was surprised to read about the "surprise" that an aspirin/nitric oxide-donating drug conjugate "doesn't behave as expected" (C&EN, Nov. 12, 2007, page 46). It appears that simple first-year organic chemistry and some key medicinal chemistry principles have been forgotten or overlooked by researchers who are perhaps a bit too eager to create a hybrid drug.
As was well-described in the cited primary research (J. Med. Chem. 2007, 50, 2424), Maikel Wijtmans and coworkers determined that the antitumor activity of [4-(nitrooxymethyl)phenyl] 2-acetyloxybenzoate, also known as NO-ASA, is likely due to unmasking of an electrophilic p-quinone methide by (enzymatic) ester hydrolysis of NO-ASA followed by 1,6-elimination of nitric acid from the resulting phenolate. The active compound thus generated "represents the simplest p-quinone methide conceivable." This highly electrophilic compound, rather expectedly, proceeds to wreak cellular havoc by trapping glutathione, thereby inducing apoptosis.
What is troubling to me is that clinical studies of NO-ASA have proceeded for several years, indeed that the compound was even intentionally synthesized, apparently without any medicinal chemists pausing to consider the inherent reactivity of the compound. Equally troubling is that the unveiling of completely expected chemical behavior is presented in C&EN as an unexpected "surprise."
First, it is well-known that esters tend to be metabolically unstable. Most medicinal chemists I've worked with would be immediately suspicious that a compound such as NO-ASA would survive long in an animal. To the contrary, esters are sometimes useful as pro-drugs. Second, the resulting hydrolysis product, 4-(nitrooxymethyl)phenol, is itself suspect because phenols are notorious for causing metabolic and toxicologic liabilities. Third and most important, it is obvious from past literature, though not in retrospect, that 4-(nitrooxymethyl)phenol is perfectly set up to undergo base-catalyzed elimination to p-quinone methide. Nitrates, methyl sulfates, and chlorides, for example, are all conjugate bases of strong acids and thus are excellent leaving groups. Fragmentations of this sort have been known and studied for decades.
As noted in the Journal of Organic Chemistry (1978, 43, 1197): "There is considerable literature on the base instability of o- and p-hydroxybenzyl groups, the decomposition going through quinone methide intermediates"; "We decided to prepare o- and p-hydroxybenzyl chlorides or the corresponding esters as reagents to generate alkali-removable blocking groups for photographically active compounds"; and more. Earlier references make clear both the base-instability of such compounds and their usefulness in quinone methide synthesis.
The intentional synthesis of the right compound for the "wrong" reasons is not so rare. What is rare, thankfully, is the inaccurate portrayal of basic chemistry in C&EN. Given the importance of conveying the positive and beneficial aspects of chemistry to the general public, it is vital that C&EN work just a bit harder at get-ting the chemistry right in its own news publication.
David W. Borhani
New York City
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