Transcript Structures of some Juvenile Hormones

LARGER TERPENES
Sesquiterpene - Juvenile hormones
Structures of some Juvenile Hormones:
• Juvenile Hormones regulate
development and reproduction
of an insect.
• Main role: ensure growth of
the larva, while preventing
metamorphosis.
• Are ultimately produced from
IPP and DMAPP.
Problem
Draw boxes around the isoprene units of MF.
Carbon likely added after
esterification step
Experiment Using Juvenile hormones
Effects of mosquito larvae being fed Juvenile Hormone
mimics: A. “Larvae Monster” is produced. B. Only
partial Metamorphosis into an adult mosquito is
observed.
• Juvenile hormone is produced in
the corpora allata of insects.
• It then disperse throughout the
haemolymph and act on
responsive tissues.
• Juvenile hormone is also
degraded by enzymes, leading to
suppression and ultimately
triggers metamorphosis with the
production of molting hormone.
• If fed Juvenile Hormone the larva
can still molt, but the result will
only be a bigger larva, not an
adult.
Sesquiterpene –Juvabione: A Plants
Revenge
Balsam fir tree
Balsam fir tree
• In 1965, Sláma and Williams discovered that paper towels
made from the wood of the balsam fir released vapors that
elicited a potent effect on hemipteran bugs.
• They actually mimic juvenile activity to prevent insect
reproduction and growth.
• These compounds play important roles in conifers
against insect induced trauma.
• Humans have used this idea to make insecticides.
Juvenile Hormone Mimics
Methoprene (Most popular):
Known Juvenile Hormones
(Difficult to Synthesize):
O
OCH3
O
- Used as an insecticide in water cisterns
to prevent unwanted mosquito growth.
- As used on various crops. Non-toxic to
humans.
- Unfortunately, it is suspected to be effecting the growth
patterns of lobsters through ground water run off.
Fenoxycarb:
Pyriproxyfen :
O
O
N
H
O
O
- Essentially same use as
Methoprene, however, it
is cheaper to make but is
also toxic to fish.
N
O
O
O
- Used on US cotton
crops to deter whitefly
growth. Effective against
flees on household pets.
Left: Fenoxycarb
pellets. Right:
Household flee
pyriproxyfen
spray
Question: What portions of
methoprene and fenoxycarb “map”
onto Juvinile hormone?
O
O
OCH3
O
O
methoprene
N
H
O
fenoxycarb
O
Diterpene (20C’s) – Paclitaxel and Derivatives
Cancer cell
dividing
Pacfic Yew tree
Paclitaxel (Taxol)
• Earliest account of terpines of this category is reported at 53 B.C., where the
Eburone King, Calivolcus (part of the Gallic Empire), committee suicide by
drinking Yew bark tea. Not much other history until the 1970’s.
• Originally isolated from the bark of the Taxus brevifolia (Pacific Yew), a conifer
native North America by Aurthor Barclay who was collecting potential cytoxic
natural samples and thought there might be some truth to the “Calivolcus
story”.
• Is extremely toxic to humans (lethal at 20 mg/kg).
• It is also one of the most commonly used chemo-therapeutic agents, and is
used for: lung, ovarian, breast cancer, head and neck cancer, and advanced
forms of Kaposi's sarcoma.
Paclitaxel and Cancer
Microtubules are responsible for separating
Chromosomes during cell division
Taxol-(b-Ala)2-PG in Hela cells
• Paclitaxel is extremely toxic for a good
reason: Taxol strongly binds to β-tubulin
and stabilizes microtubule formation.
(Please read 210 and 211 carefully).
• This disrupts the transition from Metaphase to
Anaphase during cell division as the microtubules
simply can’t degrade.
• Additionally, stabilizing microtubules inhibits other
cellular processes such as secretion of certain
critical proteins.
• The cell recognizes a problem and
undergoes apoptosis (cell suicide).
Total Synthesis of Pacitaxel: Nicolaou 1994
Spotlight Reaction:
Silyl Ethers as Protection Groups
• First introduced in the 1970’s, but highly unsuccessful. The reaction
process was markedly improved through chemistry in E. J. Corey’s lab
who is now credited with the practical use of silyl ethers for synthesis.
• Tert-butyldimethylsilyl group (TBS) was the first heavily utilized group,
but now there are a range of silyl groups to match the molecule for
ease of adding and removing the group.
• These groups are designed to contain different degrees of steric bulk.
• For the most part, silyl groups are added to an alcohol through the silyl
chloride, and are removed either using an acid or by fluoride.
Installation:
R
+ Cl Si R
R
silyl chloride
alcohol
OH
Base
Removal:
R
O Si R
R
R
O Si R
R
DMF or CH2Cl2
silyl ether
silyl ether
HCl, HOAc, or
other acid
or
R
+ HO Si R
R
alcohol
silanol
OH
HF or Fluoride
(F-) source
Example in synthesis:
OH O
+
Cl Si
Base: Imidizole
TBSO
O
TBSO
OH
2. H3O+
DMF
(TBS group)
1. CH3MgBr
(protected
silyl ether)
CH3
HCl
OH
OH
CH3
(TBS is removed)
Spotlight Reaction:
Silyl Ethers as Protection Groups
General Guidelines:
• 1o alcohols use: TBDPS or if
hindered OH group use TBS
• 2o alcohols use: TBS or if
hindered OH group use TES
• 3o alcohols use: TES or if
hindered OH group use TMS
Common Protecting Groups:
Sterically
Hindered Example:
Typical
Example:
OH
1o alcohol
OH
R
R
or
OH
R
R R
OH
o
2 alcohol
R
R
R
OH
R
R R
OH
2o alcohol
R
R
R
Use in Taxol Synthesis:
OH
R
R or
R
R
OH
R
R R
R
OH
R
R or
R
R
R
Pair the correct silyl protection group with
the alcohol most appropriate for its use
TBDPS
TBS
TBS
TMS
TES
TBDPS
TBS
TES
TMS
Explain why in the Synthesis of Taxol,
the TES protection group is more easily
removed than the TBS group.
Both alcohols silyl protected are 2o and hindered to nearly
the same degree. However, TES is less bulky of a silyl
protection group and therefore will be remove more readily
in the presence of an acid (in this case HF/Pyr).
Other Total Syntheses of Pacitaxel
Robert A. Holton’s Synthesis:
Robert A.
Holton
Other major syntheses: Danishefsky (1995-Columbia), Wender (1996-Stanford),
Mukiayama (1997-Tokyo University), Kuwajima (1998- Tokyo Institute of Technology)
Overcoming Issue #1 with Pacitaxel
Issue #1: Pacitaxel is terribly insoluble in water and many
organic solvents.
Why this is an issue: To administer most drugs they must be
in a homogenous solution otherwise the drugs effects
become less reliable.
Solution #1: Find the right
combination of solvents to dissolve
Pacitaxel.
Magic Combination: Ethanol and
Cremophor EL (like castor oil).
Downside: Tends to result in
hypersensitivity in some patients.
Solution #2: Find/Produce an analog
of Pacitaxel with same activity but
better solubility.
Result: Taxotere
Acetate group is
not present
Contains tertbutyl group
instead of phenyl
Taxotere is considerably more soluble in aqueous solutions than is Pacitaxel. As a result,
Taxotere is considerably more popular bringing in roughly 3x the annual sales as Pacitaxel.
Overcoming Issue #2 with Pacitaxel
Issue #2: Without synthesis, Paclitaxel must be obtained
from bark from the Pacific yew, the harvesting of which
kills the tree in the process.
Why this is an issue: It is estimated that annually
7,000 lbs of bark would be needed to supply the world
need for Paclitaxel. As this rate the Pacific Yew tree would
become extinct in a matter of decades.
Solution : The closely related European
Yew tree’s pine needles contains a
molecule called 10-deacetylbaccatin,
which is actually formed in Robert A.
Holton’s synthesis of Paclitaxel.
Paclitaxel can then be produced from by
harvesting 10-deacetylbaccatin and using
a synthesis developed by Robert Horton
and Iwao Ojima to make Paclitaxel.
10-deacetylbaccatin
Pacific Yew Tree bark
being harvested
European Yew Tree
Pacitaxel’s and Taxotere Current Production
Steps
3000 kg of European
Yew Pine Needles
10-Deacetylbaccatin
(1 kg)
Steps
European Yew
Needles can be
harvested without
killing the tree. As a
result, this resource
is renewable!
Paclitaxel
Steps developed by Robert Holton
and Iwao Ojima
Iwao Ojima
Taxotere
Robert Holton
Other Top Selling Anticancer Drugs
Other Top Selling Anticancer Drugs
The “Holy Grail” of Cancer Research
Mission: Obtain cancer drugs that selective kill cancer cells
and not all rapidly dividing cells.
Example of one drug: Gleevec which targets Tyrosine Kinases
(expressed in much higher levels in cancer cells than in normal dividing cells)
Considered the “miracle drug” for chronic myelogenous leukemia. In clinical trials, 53
out of 54 patients recovered after administering the drug for 4 weeks. Clinical trials were
cut short for this drug claiming that is was unethical to keep it in trials. Today, it is about
90% effective!