William N. Lipscomb, Harvard University, (approx. 2006)
. Our X-ray
diffraction study (Ref. 1) of vincristine methiodide in 1965-1966
established the correct absolute, and revised some ofthe configurations
of the ten asymmetric centers. The same configuration stereochemistry
occurs in the closely related vinblastine. Because of the complexity,
the total synthesis was not complete until year 2004 (Ref.2 and 3).
Vinblastine treats some lymphomas, Kaposi’s sarcoma and advanced testicular and breast cancer.
Ref.1. Moncrief and Lipscomb, Acta Cryst., 21
, 322 (1966).
Ref.2. Kuboyama, et al., Proc. Natl. Acad. Sci., U.S.A. 101
, 11966 (2004).
Ref.3. Mangeney et al., J Am. Chem. Soc., 101
, 2243 (1979).
2. Captopril, an ACE inhibitor
Angiotensin convening enzyme (ACE) removes a dipeptide from the
decapeptide angiotensin I (which does not raise blood pressure) to
yield an octapeptide angiotensin II (which raises blood pressure). Thus
an inhibitor of ACE would lower abnormally high blood pressure. When
Ondetti, Rubin and Cushman (Ref.4) of Squibb developed the drug
captopril, the structure of ACE (a membrane bound zinc enzyme) was
Hence they employed our zinc enzyme, carboxypeptidase A, enlarging its
active site (Ref.4). This is the first successful design of an
inhibitor using the three dimensional structure of an enzyme. At the
present time many effective pharmaceuticals are designed using this
Ref.4. Ondetti, Rubin and Cushman, Science, 1996
, 441 (1977). [Ondetti died Sept. 23, 2004 at age 74].
Ref.5. The structure is now known: Natesh, et al, Nature, 421
, 551 (2003).
3. FBPase amd Type 2 Diabetes.
Fnictose-1,6-bisphosphatase (FBPase), the penultimate enzyme in the
pathway that makes glucose, is an allosteric enzyme inhibited by
adenosine monophosphate (AMP) at the allosteric site. Our interest was
to elucidate the mechanism of control of the active site by binding of
AMP at a distant regulatory site (Ref.6 and 7).
Then, Mark Erion of Metabasis Therapeutics and I began a collaborative
project to reduce the abnormial increase of FBPase (Ref.8) shown in Type
2 Diabetics by making analogues of the inhibitor AMP. During this 15
year collaboration, we have discovered oral AMP analogues which
displace AMP, have low toxicity, do not interfere with critical other
AMP functions, and especially that reduce glucose levels to moderate
values. Studies of effective results in the rat model are summarized in
Erion, et al. (Ref`.9). Human trials are in the final stages of phase
2, and possible interactions of a promising inhibitor with metformin (a
medicine for Type 2 diabetes) are under evaluation.
Ref.6. Ke, etal., Proc. Natl. Acad. Sci., U.S.A. 87
, 5243 (1990).
Ref.7. Ke, et al., Biochemistry, 30
, 4412 (1991).
Ref.8. Rothman, et al., Science, 254
, 573 (1991).
Ref.9. Erion, et al., Proc.Natl.Acad. Sci., 102
A partial version
of this document is publshed online at the Nobel Laureate Meetings at Lindau in 2006. - JL