MED CHEM1 (Leusch)-MOD 01

Rx name?

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Papaverine

 

[erectile dysfunction]

papaver somniferium

opium poppy derivative

Rx name?

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Digoxin

[heart failure, supraventricular arrythmias]

digitalis purpurea

red foxglove derivative

Rx name?

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Artemether

[malaria]

artemesia annua

(natural products)

1. Mixture of compounds from plants, herbs, vegetables are _________

2. and defined chemical entites that are small molecules[MW <2,000 g/mol] isolated from biological sources{plants,bacteria,fungi} are__________

1. Herbal remedies/Botanical Dietary Supplements

 

2. Single Agents/Drugs

True or False

 

Drug development is a 10-17 year process with a less than 10% success rate

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True or False

 

Drug repositioning is a 3-12 year process with reduced safety and pharmacokinetic uncertainty

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This act exempted dietary supplements from regulation as drugs, provided they are NOT MARKETED FOR Dx, Tx, CURE, or DISEASE PREVENTION

[Do not require premarketing approval by the FDA]

Dietary SUpplement and Health Education Act (1994)

True or False

 

Dietary supplements do not require proof of efficacy

 

Dietary supplements are exempt from good manufacturing practices (GMP)

 

Manufacture self regulate dietary supplements and are marketed until proven unsafe

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This dietary supplement was found to be contaminated with an anti-prostate cancer prescription medication and was marketed from 1996-2002

(7 botanicals, 1 fungus)

PC-SPES

 

Echinacea

[Herbal Remedy]

antiseptic, antiviral, immunostimulant

Evening Rose

[Herbal Remedy]

premenstrual tension

Feverfew

[Herbal Remedy]

migraine

Garlic

[Herbal Remedy]

Lowers cholesterol, antimicrobial

Ginger

[Herbal Remedy]

motion sickness, nausea

Ginkgo (Ginkgo Biloba)

[Herbal Remedy]

anti-inflammatory, circulatory disorders, dementia

Ginseng

[Herbal Remedy]

Stress & Fatigue

Valerian and Hops

[Herbal Remedy}

Sedative, sleep disturbances

Saw palmetto

[Herbal Remedy]

prostate

 

(shrinks the inner lining that puts pressure on the tubes that carry urine.)

 

St John’s Wort

[Botanical Dietary Supplement]

 Contains hypericin and Hyperforin

Anti-depressant, anti anxiety

 

***produces CYP’s (enzyme that induces metabolism of other drugs)

***This interacts w/ other prescription Rx’s

Rx name?

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Hyperforin

[inhibits neurotransmitter uptake]

(1 of 2 compounds responsible for st johns wort’s activity)

Rx name?

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Hypericin

[inhibits several kinases and dopamine B-hydrolase {increased dopamine levels}]

(1 of 2 compounds responsible for st johns wort’s activity)

side effect= photosensitivity

Rx name?

 

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Methysticin

[anticonvulsant, neuroprotective properties]

(a kavalactone)

 

Octanol mimicks the lipid phase of a cell membrane well. Seperating a drug using Octanol and water provides us with a log P. What is log P called?
Partition Coefficient

Name this functional group

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Epoxide
These 3 functional groups are very reactive and should be omitted when creating new drugs

1. Epoxide

 

2. Catechols [form unsaturated quinones to react w/ proteins]

 

3. Carbocations [damage DNA by introducing mutations]

 

True or False

 

Natural products tend to have more stereocenters (chiral) than synthetic products

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Rx name?

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Pulegone

mentha pulegium

[relieves menstrual Sx’s, feverish colds]

from Pennyroyal oil

 

 

Rx name?

This is derived from Pulegone 

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Menthofuran

***highly toxic and believed to be the primary toxin in Pennyroyal. liver/lung damage 

Rx name?

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Safrole

[diuretic, weakly carcinogenic]

 

Obtained from steam distillation from bark and roots of Sassafras albidum

What is NRF2?

Why important?

It is a transcription factor.

 

It is carcinogen-detoxifying, antioxidant protein properties, and protects against aging and disease.

Rx name?

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Aspirin (aka acetylsalicylic acid)

[NSAID, antiplatelet]

 

from wllow tree

 

Rx name?

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Morphine

[strong opioid analgesic]

 Alkaloid

from Opium poppy seed pods

Rx name?

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Taxol

[anticancer]

 Terpene

from pacific yew tree

Rx name?

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Vincristine

[Anti-cancer]

from Madagascar periwinkle

 

Rx name?

[image]

Doxorubicin

[anticancer]

Rx name?

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Cyclosporin A

[eye drops for dry eye Tx, immunosuppressant]

Polypeptide

What are the 7 major issues for natural product development?

 

***Hint=Neumonic is SRTENTI (Certainty)

Supply-NP’s product is minor

Reproducibility-hard to find real producer[microbe or source?]

Expense-building and maintaining extract

Time-tedious isolation

Novelty-unpredictable

Tractability-SAR complex

Intellectual Property-authorization to collect in foreign countries

Rx name?

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Cocaine

 

[Class I scheduled stimulant]

Rx name?

[image]

Benzocaine

[cocaine derivative]

Rx name?

[image]

Benzoyl atropine

[cocaine derivative, local anesthetic]

Rx name?

 

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Procaine (AKA Novocaine)

[cocaine derivative, local anesthetic]

esters

Rx name?

[image]

Tetracaine

[cocaine derivative, local anesthetic]

esters

Rx name?

[image]

Lidocaine

[cocaine derivative, local anesthetic]

amides

Rx name?

 

[image]

Bupivacaine

[cocaine derivative, local anesthetic]

Amides

Malonyl COA is made in claisen condensations an form 1,3 ketones and alcohols in_________________

[image]

Polyketides

 

Molecule name?

[image]

Tetracycline

[Bacterial metabolite]

polyketide from bacteria

Rx name?

[image]

Rapamycin

[antifungal, immunosupressive]

polyketide from bacteria

Rx name?

[image]

Avernectin a1a

[anthelmintic]

polyketide from bacteria

Rx name?

[image]

Amphotericin B

[antifungal]

polyketide from bacteria

Rx name?

 

[image]

 

Nigericin 

[antifungal]

polyketide ffrom bacteria

_______________’s are characterized as molecular structures with carbon units in multiples of 5 with branching at the C2 postion.

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Isoprenoid/Terpenes

 [many plant secondary metabolite]

ex:limonene,menthol,taxol,taxadiene

(come as C5, C10, C15,……..)

____________’s have N’s with negative oxidation states, are basic, heterocyclic molecules. 

 

ex:) codeine, morphine,…

ALKALOIDS [mainly plant product]

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____________’s are molecule characterized by fusing together amino acids.

 

ex:)cyclosporin A, dolastatin

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PEPTIDES

[mainly produced by bacteria and fungi]

Name?

[image]

Limonene

 

monoTerpene

Name?

[image]

amorphadiene

[sesquiterpene]

Name?

[image]

Taxadiene

{diterpene}

Name?

[image]

Menthol

[terpene]

Rx Name?

[image]

Artemisinin

[terpene, antimalarial]

Name?

[image]

Dopamine

(precursor to alkaloid)

Rx name?

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Codeine

[opioid analgesic, cough, anti-diarrheal]

Alkaloid

Poppy seed derivative

Rx name?

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Dolastatin 10

[anticancer]

Hybrid polypeptide-ketide

FDA approved as ADC=antibody drug conjugate

WHat protion of drugs are natural product derived?

50%

 

(99% of organisms/secondarymetabolites=unexplored)

Rx name?

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Cytarabine (aka Cytosar-U)

[anticancer]

marine drug

Rx name?

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Ziconotide (aka Prialt)

marine drug

[analgesic, epilepsy]

*****100-1,000  times more potent than morphine

Rx name?

[image]

Eribulin Mesylate (aka Halaven)

marine drug

[metastatic breast cancer]

Rx name?

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Vidarabine (aka Vira-A)

marine drug from sponge

[antiviral]

Rx name?

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Trabectedin (aka Yondelis)

[anticancer]

marine drug

Rx name?

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Brentuximab Vedotin (aka Adcetris)

[anticancer]

 

Marine organisms are associated with____________in symbiotic relationships. These other organisms are responsible for the majority of biosynnthetic drugs extracted from marine organisms.
BACTERIA

Rx name?

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Cyanosafracin B

[DNA interacting compound]

marine drug

 

***semisynthetic trying to replicate anticancer drug Yondelis

 Rx name?

[image]

Bryostatin 1

[anticancer, binds protein kinase C]

marine drug

 

***was not feasible to replicat due to complex structure in 1990. An analog was made in 2003

Rx name?

[image]

Didemnin B

Polypeptide-ketide

[anticancer]

Marine drug from Tridemnum Solidum

 

***was too toxic.analog (APlidine was made and is in clinical trials)

Rx name?

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Aplidine

[anticancer in clinical trials]

Marine drug

Analog of Didemnin B

****alcohol was changed to ketone

Rx name?

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Salinosporamide

[anticancer]

Marine drug

Has chloride(key feature in reacting w/ proteosome)

Rx name?

[image]

Bortezomib (aka Velcade)

Marine Drug

[multiple myeloma 2003]

***proteasome inhibitor

Rx name?

 

[image]

Carfilzomib

Marine drug

[multiple myeloma 2012]

analog of epoxymycin

***proteasome inhibitor

 

Largazole depicted below. Is it active or is it a prodrug?

 

[image]

Largazole is a prodrug activated by hydrolysis at the thioester.

Marine drug anticancer

(discovered at UF!)

Drug name?

[image]

Vorinostat (aka Zolinza)

[T-cell lymphoma]

 

Natural product

SAHA (aka Suberoylanilide hydroxamic acid)

HDAC inhibitor

Rx name?

[image]

Romidepsin (aka F228)

[CTCL or Cutaneous T-cell Lymphoma 2009]

 

HDAC inhibitor

PRODRUG!

Purely NATURAL COMPOUND!!!!

 

****activated by glutathione mediated reductase

1. p53 and pRb are ________________

 

2. WHile p21 is an __________________

1. Tumor suppressing transcription proteins

 

2. Endogenous cell cycle inhibitor/controller

What does HDAC stand for and what do they do?

HDACs are histone deacetylases and are responsible for the deacetylation of histones in the chromosome structure. 

Contain zinc catalytic binding domains.

How can we improve the therapeutic index of existing drugs for cancer therapy?

 

A. Design improved analogues

B. Assure delivery only to target

C. Both a and b

D. Using Morphine Bioisosteres

C. Both a and b

How can we find a disease relevant protein (to be inhibited or activated)?

 

Screen molecules/natural products against this target (or block activity w/ antibody)
What does ADC stand for?

Antibody-Drug Conjugates

 

They are conjugated monoclonal antibodies used against molecules selectively expressed in cancer cells.

Rx name?

[image]

Calicheamicin(ADC)

[cancer drug w/ antibody]

 

***Approved in2000 but pulled from market in 2010

Knocking down, using an arrayed siRNA library, reporter cells, and a genome wide interrogation of gen function all describe_________________.

Screening

[for gene products that control disease-associated transcription factors]

1. The druggable genome consists of approximatley how many genes?

 

2. How many are targeted by approved drugs?

 

3. How many kinases controltranscription factors?

 

4. Of the druggable protein targets what % are GPCRs?

1. ~3,000

 

2. 200 genes

 

3. 518 Kinases

 

4. 15% GPCRs

These macro molecules facilitate sequence specific gene suppression via RNA interface and cause degradation of homologous mRNA sequences.
siRNA
RISCs are________
RNA induced siencing complexes

What do these methods describe?

 

-Using Knockout mice

 

-Dominant negatives

 

-siRNA use

TARGET VALIDATION
RTKs (receptor tyrosine kinases) are often overexpressed in cancers and are activated by______________
Growth factors
Tyrosine, Threonine, and Serine are substrates for ________________
Intracellular kinases
What % of cancer drugs are antibodies?
20%
HER2 (ERBB2) is overexpressed in _______% of invasive breast cancers.
20-30%

Gleevec (Imatinib, STI-571)

[image]

Tyrosine Kinase inhibitor

[anticancer]

Phenylaminprimidine back bone (PAP)

 

 

IRESSA

[image]

Receptor tyrosine kinase inhibitor

[anticancer]

Nexavar (sorafenib)

 

[image]

 

Broad spectrum RTK + Ser/Thr kinase inhibitor

[anticancer]

Rx name?

[image]

Trastuzumab (Herceptin)

[anticancer]

ANTI-Her2{anti-RTK monoclonal antibodies}

[image]

Cetuximab and Panitumumab are what type of anti-RTK monoclonal antibodies

Anti-EGFR

[anticancer]

Bevacizumab

Anti-VEGF-A

[anticancer]

Anti growth factor monoclonal antibody

This describes what? (one answer)

 

-Binds ATP, transfers phosphate group onto substrate(signaling)

-Ser/Thr ______ transfer phosphate onto certain Thr/Ser residues of substrate

-Tyr______ transfer phosphate onto Tyr residue of substrate

 

KINASE!!!

How do you inhibit a KINASE?

 

1. Allosteric inhibitors [induce conformational changes]

 

2. Occupying ATP binding sites [difficult but not impossible]

x

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