Transcript What does the transition state of this reaction look like?

What does the transition state of
this reaction look like?
• Note that a key step in the previous mechanism is the
loss of an alkoxy (sugar) moiety from the position
(C2) next to the carboxylate group.
• This creates a carbocation (Sn1 process), which is
sp2 hybridized.
• The initial substrate is sp3 hybridized at C2
• Thus it was decided to try to synthesize and test
compounds which had a double bond to C2, with the
prospect of identifying something which bound tighter
than the substrate and which could, therefore,
function as an effective inhibitor.
Chemical evolution of neuraminidase inhibitors
• Note that lower Ki values correspond to more active inhibitors
• The final product, Relenza (Zanamivir), has a positively
charged guanidinium cation (southern end of molecule)
• Thus, it is too polar to be absorbed orally and must be
administered by inhalation.
Further chemical evolution of neuraminidase inhibitors
While the C5 substituent (glycerol side chain) bound to a
polar pocket, some of the more recent analogs have
shown there is also a hydrophobic pocket, which can
bind more hydrophobic C5 side chains, such as the
tertiary amide side chain of I.
• Note that the actual reaction intermediate (lower left) involves a resonancestabilized carbocation (with oxygen providing electrons to stabilize the C2
carbocation.
• Thus it was decided that the double bond of Relenza (Zanamivir) might be in a
somewhat incorrect position for optimal binding.
• To prepare a stable compound with the double bond in the optimal position, they
had to replace the oxygen of the six-membered ring with a carbon (called a carbon
isostere).
•Note the improvement in activity as the double bond position is altered.
Further chemical evolution of neuraminidase inhibitors
• Thus a series of compounds was prepared having an
appropriately placed C=C and an adjacent hydrophobic
group (in this case a substituted ether linkage).
• The most active of these (above) has a branched side
chain (3-pentyl side chain) on the ether.
• Due to the improvement in inhibitory activity, it was
possible to remove the highly polar guanidinium side chain
and replace it with a slightly less polar amine side chain.
Evolution leading to the final product, Tamiflu.
• The carboxylic acid of GS 4071 is still too polar.
• Thus, they replaced the acid with an ester, which can be
hydrolyzed by esterases.
• Compounds related to II (above) are currently in clinical
trials. These seem to show a further improvement in
selectivity against viruses.
What is HSV?
• HSV = Herpes Simplex Virus
• HSV-1 is the ‘usual’ cause of cold sores
• HSV-2 is the ‘usual’ cause of genital
herpes
• Both types look the same under the
microscope and share about 50% of
their DNA.
Major members of the herpesvirus
group of the family Herpesviridae
• Herpes simplex viruses: HSV-1 and
HSV-2
• Cytomegalovirus (CMV)
• Varicella-zoster virus (VZV)
• Epstein-Barr virus (EBV)
Varicella-zoster virus (VZV)
• The Varicella zoster virus (VZV) is one of
the eight herpes viruses known to affect
humans (and other vertebrates). It
commonly causes chickenpox in children
and shingles later in life.
Shingles
Treatment of Varicella Infection
• Acyclovir has been shown to reduce fever
and skin lesions in patients with varicella
and it use is recommended in healthy
patients over 18 years of age.
Acyclovir (ZOVIRAX)
Cytomegalovirus
• Cytomegalovirus (CMV) is a common virus
that infects most people during their life.
Most people are infected in early childhood
(under 3 years of age) or in the teenage
years. Usually there are no symptoms of
CMV infection. Since most CMV infections
are mild and usually do not cause long-term
problems, most people don't even know they
are infected. However, CMV can cause
problems in a developing baby if the mother
gets the infection during pregnancy.
Cytomegalovirus (CMV)
• After a person has a CMV infection, the
virus stays in the body but is not active.
The virus can reactivate months or
years later, which occurs most often
when a person's immune system is
weakened.
Cytomegalovirus (CMV)
• Anyone with a weakened immune system is
at risk for problems with CMV infection. A
weakened immune system can be related to
infection with the human immunodeficiency
virus (HIV) or medical treatments. Medical
treatments that can weaken the immune
system include: chemotherapy, radiation
therapy, steroids, and stem cell or organ
transplantation.
Cytomegalovirus (CMV)
• A few people will have symptoms such as sore throat,
fever, headache and fatigue. People who have
weakened immune systems may develop severe
symptoms, such as pneumonia or infections of the
eyes, liver, or intestinal tract. People with HIV
infection should be sure to let their doctor know if
they are having any painless blurring of their vision,
"floaters" in the eye, light flashes, areas of blindness,
or shortness of breath.
Treatment of CMV Infection
• Gangiclovir, a nucleoside analog of acyclovir,
inhibits CMV replication and reduces the severity
of CMV syndromes, such as retinitis and
gastrointestinal disease.
O
N
HN
H2N
O
O
N
HN
N
N
H2N
HO
N
N
O
OH
Deoxyguanosine
H2N
N
N
HO
HO
O
N
HN
O
OH
Acyclovir
Gangiclovir
Epstein-Barr Virus (EBV)
• EBV is the etiologic agent of infectious
mononucleosis
• Symptoms include fever, tender lymph
nodes, sore throat, mental fatigue
• Treatment is usually supportive
• Acyclovir can decrease replication of
EBV in culture, but has little impact on
clinical illness.
HSV-1 and HSV-2
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