L ETTERS
istry (1978, 43, 1197): “There is considerable
THE SURPRISE THAT WASN’T
I WAS SURPRISED to read about the
“surprise” that an aspirin/nitric oxide-do-
nating 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 chemis-
try principles have been forgotten or over-
looked by researchers who are perhaps a bit
too eager to create a hybrid drug.
As was well-described in the cited pri-
mary research (J. Med. Chem. 2007, 50,
2424), Maikel Wijtmans and coworkers de-
termined that the antitumor activity of [4-
(nitrooxymethyl)phenyl] 2-acetyloxyben-
zoate, 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 “rep-
resents the simplest p-quinone methide
conceivable.” This highly electrophilic
compound, rather expectedly, proceeds to
wreak cellular havoc by trapping glutathi-
one, thereby inducing apoptosis.
What is troubling to me is that clinical
studies of NO-ASA have proceeded for sev-
eral 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 unex-
pected “surprise.”
First, it is well-known that esters tend
to be metabolically unstable. Most me-
dicinal chemists I’ve worked with would
be immediately suspicious that a com-
pound such as NO-ASA would survive
long in an animal. To the contrary, esters
are sometimes useful as pro-drugs. Sec-
ond, 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. Fragmenta-
tions of this sort have been known and
studied for decades.
As noted in the Journal of Organic Chem-
WWW.C E N- ONLI NE .ORG
literature on the base instability of o- and
p-hydroxybenzyl groups, the decompo-
sition going through quinone methide
intermediates”; “We decided to prepare
o- and p-hydroxybenzyl chlorides or the
corresponding esters as reagents to gener-
ate 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 convey-
ing 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
MTBE SOLUBILITY CONCERNS
IN RESPONSE TO Jonathan Targett’s
letter, methyl tert-butyl ether (MTBE) is
indeed far less toxic than benzene, but it
is also far more soluble in water (46 g/L)
(C&EN, Dec. 10, 2007, page 2). As a result,
it spreads in groundwater from gas station
leaks faster and farther than benzene.
A gasoline leak in Port Hueneme, Calif.,
resulted in an MTBE plume covering 36
acres, whereas the plume of benzene, tolu-
ene, ethylbenzene, and xylenes (BTEX)
covered only 9 acres. The Environmental
Protection Agency drinking water advisory
limit for MTBE is 20–40 μg/L; it is tasteable
at 40 μg/L. A gas station leak in my own
community resulted in MTBE being above
the EPA advisory limit in several domestic
wells, but BTEX was not. The latter is also
readily metabolized by soil microorgan-
isms. MTBE-utilizing organisms were not
detected until 1994, though they are now
common and even used commercially to
remediate MTBE in groundwater.
Ethanol, of course, has replaced MTBE
not so much for smog reduction as because
it is a renewable fuel produced from crop
feedstocks—possibly increasing the cost of
foods produced from corn, including beef
and pork.
Theodore Chase Jr.
Princeton, N.J.
4 FE BRUARY 4, 20 0 8
RISKY BUSINESS
“RISKS FROM FOREIGN Drug Imports”
describes a very alarming situation (C&EN,
Nov. 26, 2007 page 38). However there is no
mention of who is doing the importation
and whether those companies do anything
to ensure the quality of the product before
it is dispensed to the public.
Major pharmaceutical companies are
not going to risk dispensing bad product.
Why not follow up on what safeguards
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pharmaceutical companies offer and not
make the Food & Drug Administration our
savior, which you so adequately disclose?
Edward H. Gleason
Ooltewah, Tenn.
CONFLICTS OF INTEREST
IN “EMPOWERING FDA,” the discussion
about advisory panel members with con-
flicts of interest says, “It is not a good idea
to keep experts off advisory committees
simply because they have conflicts of inter-
est” (C&EN, Dec. 3, 2007, page 33).
I agree that members with conflicts of
interest have valuable expertise. Why not
allow a limited proportion of members with
conflicts of interest on any given commit-
tee, say 20% maximum? To avoid problems,
these members would not be able to vote.
For example, there is an association
of building code officials for people who
enforce the construction of buildings in ac-
cordance with various building codes. This
association welcomes members from the
regulated community, such as architects
and builders, but does not allow them to
vote. Letting the regulated community
vote on measures that affect them is con-
sidered a conflict of interest. The building
code officials’ organization benefits from
the expertise of the members with conflicts
of interest, but things are kept on the up-
and-up because these particular members
can’t vote.
Geoffrey Miller
Belsano, Pa.
PLASTICS RECYCLING
ALEXANDER TULLO’S ARTICLE on re-
cycling prompts me to mention another
aspect to plastic recycling that wasn’t
touched on in his article (C&EN, Oct.15,
2007, page 15). It certainly appears that re-
cycling bottles and other containers would
increase significantly with more public
education, but there is one area in which
the packing industry needs to be made to
take action.
I’ve been frustrated for some time over
the lack of identification of the plastics
used in all sorts of bags and wrappers,
such as those for potato chips, birdseed
and pet food, vegetables and fruit, meats
and cheeses, and the internal wrappers
in cracker and cookie boxes. The packing
industry should be required to identify all
these materials for the purpose of recy-
cling. Perhaps laws have to be passed to
close this loophole in plastic recycling. I
was surprised to find upon surveying my
household that 80% of the bag packages
had no recycling identification.
Stan Manatt
La Cañada, Calif.
MORE ON CHEMOPHILATELY
THANK YOU SO MUCH for a very enjoy-
able article on chemophilately (C&EN,
Dec. 17, 2007, page 29). For those who are
interested in further reading, “A Philatelic
Ramble through Chemistry,” by Edgar Heil-
bronner and Foil A. Miller was published by
Wiley-VCH in 1998.
Rita Majerle
St. Paul, Minn.

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