Terpenes, Antihyperlipoproteinemics, Alkaloids, Natural Products

NATURAL PRODUCTS

1. Natural products have ______ molecular weights than synthetics

2. _________ oxygen content

3. _________ atoms of N, S, or halogen

4. _________ number of rings, chiral centers, and sp³-hybridized bridgehead atoms

1. higher

2. more

3. less

4. larger

Lipinsky Rules → POOR absorption/permeability when:

1. cLogP is _____

2. molecular mass is ______

3. # of H bond DONORS (OH + NH) is ________

4. # of H bond ACCEPTORS (O + N) is ________

5. HOWEVER, these rules DO NOT apply to ________________

1. >5

2. >500 Da

3. >5

4. >10

5. natural products

____________: the study of natural product molecules (typically SECONDARY metabolites → important for the survival of plant species, but not required in ALL plant species)

pharmacognosy

The natural species that are the source of the compounds under study span all biological kingdoms, MOST NOTABLY → 4

1. marine invertebrates

2. plants

3. fungi

4. bacteria

TERPENES

1. Many terpenes are _________, but oxygen-containing compounds (alcohols, aldehydes, ketones) are also found

2. Building block = _____________ linked in head → tail fashion

1. hydrocarbons

2. isoprene

1. monoterpenes

2. sesquiterpenes

3. diterpenes

4. sesterpenes

5. triterpenes

6. carotenoids

7. polyterpenes

What kind of terpenes are major components of fragrant oils (perfumes, flavorings)?

monoterpenes

1. CAMPHOR’s mechanism of toxicity is unknown, but it possesses both __________ and ___________ activity

2. Death is secondary to _____________ or _________

3. Camphor LogP?

1. excitatory, depressant

2. respiratory failure, seizures

3. 2.38

_______________: therapeutic use of aromatic substances extracted from plants (essential oils)

aromatherapy

The use of aromatherapy during pregnancy, particularly the _____________ should be AVOIDED

1st trimester

___________________: bicyclic monoterpenes, they are some if not the most bitter of all compounds, often responsible for the so-called “bitter principle” of a plant

iridoid glycosides

_____________ → _________ natural product example that has traditionally been used as a sedative, has CNS-depressant activity, and +GABA

Valerian, iridoid

SESQUITERPENES (C15)

wide distribution in nature, form the largest class of terpenes

1. provides plant protection as _________ and ________

2. __________ from cotton plant → antifertility agent in men, acts on testicular mitochondria

3. __________ → used for sleeplessness, anxiety, GI conditions, skin conditions + mouth ulcers resulting from cancer tx

4. Sesquiterpene lactone: _______________ → treatment of malaria

1. antimicrobial, insecticidal

2. Gossypol

3. chamomile

4. artemisinin

_______________ is the major component of chamomile oil, it is believed to be responsible for some of the effects of chamomile

bisabolol

The ____________ in artemisinin is essential for antimalarial activity, This compound is very _________ and well absorbed in the CNS

peroxide, lipophilic

Suffix “_______” indicates presence of a lactone group

-olide

Many members of the Asteraceae family are known to cause _________________ in humans

Sesquiterpene lactones react with _________ receptors

contact dermatitis, nucleophiles

1. The leaves of _________ (Tanacetum parthenium) have been used for the treatment of headaches. Originated in Europe and is a member of the sunflower family (Asteraceae)

2. Suspected to have antiplatelet effects and thus might cause excessive __________ if used preoperatively → *tell patients to DC at least 2 weeks before elective surgical procedures

3. Limitation → potential toxic effect of _________ observed in some patients e.g. mouth ulceration or hepatotoxicity

1. feverfew

2. bleeding

3. SL

DITERPENES (C20)

1. _________ (rebaudioside A) → noncaloric sweetener

2. _________ (Paclitaxel) → breast cancer chemotherapy → natural production too slow, now produced semi-synthetically from baccatin

3. _________ → potentially beneficial effects for patients w dementia, insufficient evidence in preventing dementia

1. Truvia

2. Taxol

3. ginko biloba

Ginkgo biloba has 2 primary active ingredients:

1. diterpene lactones (___________)

2. ginkgo flavone glycosides (__________)

3. What kind of terpene?

1. ginkgetin

2. bilobetin

3. diterpene

________ are included in the group of triterpenes (C30)

steroids

____________ → metabolic regulators, +resistance to harmful factors/stressors, typically no side effects unlike traditional stimulants (addiction, tolerance, abuse potential), NO FDA APPROVED

Example →

adaptogens → ginseng

Claims/uses of GINSENG

1. Support overall health and boost ___________

2. +sense of _________ and _________

3. improving both ______ and ______ performance

4. Treating _________

5. lowering _______ and controlling _______

6. Most common side effects → 3

1. immune sys

2. well-being, stamina

3. mental, physical

4. ED

5. blood glucose, BP

6. headaches, sleep problems, GI

Ginseng Drug Interxns

1. Likely → 2

2. Possibly → 4

1. anticoagulants, antidiabetics

2. MAOI, antipsychotics, cardiac glycosides, BP meds

Advise patients NOT to take American ginseng w __________ (-effectiveness)

warfarin

Ashwagandha → adaptogenic, sedative, tonic, mood booster

Advise patients with ____________ to AVOID/use with caution

autoimmune diseases

Cholesterol Biosynthesis + Biotransformation

1. _____________ reduces the CoA thioester to mevalonic acid (primary alcohol)

2. Cholesterol → pregnenolone by ____________

3. Pregnenolone is a common intermediate for biosynthesis of ________ hormones

4. Cholesterol also converted to ________ and _______ → difference?

5. Cholesterol converted to cholic acid (a bile acid) by __________ enzyme

1. HMG CoA reductase

2. 20,22-desmolase

3. steroid

4. bile acids → 75% gly + 25% taurine, bile salts → anionic detergents (emulsify dietary lipids + fat-sol vitamins)

5. 7a-hydroxylase

Name the primary function

1. Chylomicrons → transport ____________

2. Chylomicron remnants → transport ____________

3. VLDL → transport _____________

4. IDL → transport _____________

5. LDL (Bad) → transport _______________

6. HDL (Good) →

1. dietary triglycerides

2. dietary cholesterol

3. endogenous triglycerides

4. endogenous triglycerides

5. endogenous cholesterol

6. REMOVE cholesterol from extra hepatic tissues

Drugs affecting LIPOPROTEIN → 4

1. bile sequestrants

2. HMG CoA reductase inhib

3. fibrates

4. nicotinic acid (niacin)

BILE ACID SEQUESTRANTS

1. Cholestyramine and Colestipol are __________________ (+ charged polymer resins that BIND to - groups

2. Cholestyramine originally used in patients with ____________ (when flow of bile from liver is reduced)

3. MOA: not absorbed in GI tract, sequester bile acids in the ___________ → prevent reabsorption and +excretion → -[bile acid] in liver

4. ______________ is indirectly lowered by these drugs by +rate that it is cleared from blood

1. anion exchange resins

2. cholestasis

3. intestine

4. plasma LDL

1. The total nitrogen content of COLESTIPOL per gram is ________ than that for cholestyramine, however

2. Its functional anion exchange capacity may be less since colestipol depends _________ of the intestine.

3. Bile salt adsorption capacity comparison

1. greater

2. upon pH

3. cholestyramine > colestipol

Colestipol and Cholestyramine

1. Drug class

2. Contraindications: → 2

3. Drug interxns →

1. BA sequestrants

2. hypertriglyceridemia, cholelithiasis (gallbladder stones)

3. may -abs of drugs = admin other meds 1h before OR 4-6h after

1. HMG CoA reductase inhibitors are known as ___________

2. The first 2 drugs =

3. Prodrug that is activated by in vivo ____________________

4. Active drug mimics ________ intermediate produced by HMG CoA reductase

5. Enhanced ________________ may be the primary mechanism for lowering plasma LDL levels

6. Unlike the others, ______________ decreases plasma LDL in pts w homozygous familial hypercholesterolemia

1. statins

2. mevastatin, lovastatin

3. hydrolysis of lactone ring

4. tetrahedral

5. LDL receptor expression

6. atorvastatin (Lipitor)

HMG-CoA reductase inhibitors SAR

1. The _____________ is essential for inhib activity

2. ________________ ring essential for anchoring the compound

3. ^ Replacement w cyclohexane ring = ____________ in activity

4. ___________ can inc/dec activity

5. Ester side chain → ether = _____ activity

6. _________ +activity 2x

1. 3,5-dihydroxycarboxylate

2. unsat decalin

3. 10,000 fold dec

4. double bond C7/8

5. dec

6. methyl R2

PK considerations for HMG-CoA reductase inhibitors

1. Food does NOT affect absorption → EXCEPT ________

2. Should be admin at _______________ to counteract peak cholesterol synthesis that occurs in early morning

3. ________ effective regardless when admin bc of long half-life

4. May be used alone OR in combination with ___________ or ___________ (1h before or 4-6h after for BA sequestrants)

5. *CONTRAINDICATIONS →

6. ADVERSE EFFECTS → 3

1. lovastatin

2. bedtime/evening

3. atorvastatin

4. BA sequestrants, niacin

5. pregnancy, nursing mothers

6. GI, +hepatic transaminase, +CPK (creatine phosphokinase)

HMG-CoA reductase inhibitors have a rare but serious risk of ___________

rhabdomyolysis

Mechanisms of Statin-associated Myotoxicity (muscle damage)

1. Inhibition of __________________

2. mitochondrial dysfunction → 2

3. inhibition of __________________

4. ____________

5. Inhibition of ___________ pathway

1. protein prenylation

2. inhib ETC, ubiquinone deficiency

3. mt biogenesis

4. oxidative stress

5. Akt/mTORC

NORMAL cholesterol levels:

<200 mg/dL

FIBRATES

1. 1st Drug =

2. newer and safer developed drugs = 2

3. MOA: decrease plasma __________ levels more dramatically than cholesterol levels

4. Moderately increase ________ lvls

1. clofibrate

2. gemfibrozil, fenofibrate

3. triglyceride

4. HDL

1. which fibrates are PRODRUGS and require ester hydrolysis?

2. para-substitution of aromatic ring with _________ produces compounds with significantly LONGER _________

3. _______________ group essential for activity

1. clofibrate, fenofibrate

2. Cl, t1/2

3. isobutyric acid

Nicotinic acid =

niacin = vit B3

name these

*recognize that these are NOT the same compounds, even tho their names are similar

1. nicotinic acid

2. nicotinamide

3. nicotine

Nicotinic acid MOA

1. Inhibits ___________ in adipose tissue

2. _____________ leads to -LDL → -triglyceride within several hrs, -cholesterol takes several days

3. Nicotinic acid has NO effect on cholesterol __________ or ___________

4. Increases HDL due to -clearance of __________

1. lipolysis

2. -VLDL

3. catabolism, biosynth

4. apoA-I

Nicotinic Acid (Niacin) CONTRAINDICATIONS

1. -

2. -

3. -

1. Peptic ulcer disease

2. hepatic disease

3. predisposed DM or gout

Friedrich Wilhelm Adam __________ discovered opium’s main narcotic principle, MORPHINE

serturner

1. MOST alkaloids are present forming _________ → usually ______________

2. Salts are (less/more) stable than free alkaloids

3. Basic or non basic alkaloids will be readily absorbed in stomach?

4. IV administered alkaloids are usually administered as ______

1. salts, water soluble

2. more

3. non basic

4. salts

1. Caffeine and Theobromine are CNS _________ and __________

2. Which one has LESS CNS activity?

1. stimulants, diuretics

2. theobromine

The LD50 of caffeine in humans is estimated to be about ________/kg of body mass

Reports of hospitalization after ingestion of about ________

150-200 mg, 2 g

1. Nicotine is a _____________ ___________

2. 2 enantiomeric forms → which form is more active?

3. Why does very little nicotine oral absorption occur when smoking cigarettes? (pKa = 8.02)

4. Chewing tobacco and oral snuff are made from air-cured tobacco, resulting in tobacco that has a ______ pH, which is ideal for oral absorption

1. pyridine alkaloid

2. S (-)

3. acidic smoke → ionized → -abs

4. basic

Phenylpropanoids Common Structure =

C6 unit + C3 unit attached to aromatic ring

Phenylpropenes

1. _________: plant product example

2. _________: active components

3. Use =

4. Has _______ status (generally recognized as safe)

5. *Drug interxn:

6. BioPerine is standardized black pepper extract → _____ piperine minimum and also _______ status

1. turmeric

2. curcuminoids

3. anti-inflam

4. GRAS

5. CYP3A4 + P-gp inhibitor

6. 95%, GRAS

FLAVONOIDS occur as plant pigments, often yellow or orange

Likely main role in nature is as color attractants to insects and birds, or to affect the taste of plants

Their basic chemical structure is ___________ connected by _____ link

C6 - C3 - C6

2 benzene rings, 3C

MILK THISTLE / SILYMARIN

1. commonly used for tx of ________ and _________ disorders

2. Lab studies demonstrate that milk thistle: stabilizes ________ membranes

3. stimulates __________ pathways

4. stimulates __________ of liver tissue

5. Clinical studies do NOT show any effect against _________

6. Oral milk thistle for ___________ - results promising, but better research needed

7. Also possibly effective for ________ when used in combination with conventional treatments

1. liver, gallbladder

2. cellular

3. detoxification

4. regeneration

5. hep C

6. cirrhosis

7. Type 2 diabetes

1. FLAVONOIDS have important dietary significance because being ________ compounds, they are strongly ___________

2. Flavonoids occur both free (__________) and as ___________

3. predominant conjugated metabolites = 3

4. _________ are most well absorbed (then flavanones, then quercetin glucosides)

5. _________ and _______ LEAST well absorbed

1. phenolic, antioxidant

2. aglycone, glycosides

3. glucuronate, sulfate, methyl

4. isoflavones

5. anthocyanins, proanthocyanidins

1. Anthocyanins (ACN) been consistently shown to INCREASE endothelial-derived ___________ → vascular smooth muscle relaxation via cGMP, -BP

2. ACN shown to prevent ^ __________ and radical-induced conversion

3. ACN shown to reduce synthesis of __________ molecules such as Ang II, endothelian-1, thromboxanes

4. Name the 3 food with highest ACN content

Red-purple-blue-wine color → present in certain fruits, vegetables, legumes + rice, beverages

1. NO

2. oxidative damage

3. vasoconstricting

4. blackberries, elderberries, red cabbage

STILBENES are related to flavonoids but have the basic structure ____________

C6-C2-C6

Resveratrol is naturally occurring compound found in various plant species including _________, very strong ________ and also possess anti-inflammatory and anticancer properties

grapevines, antioxidant

Phytoestrogens may inhibit the development + progression of _______________

breast cancer

Soy isoflavones provides ____________ relief by naturally relieving hot flashes and night sweats

menopause