Heterocycles (McM chapt 28)•Monocyclic or fused rings•Cont. one ore more ring atom ≠ C (normally O; N; S)•Aromatic, partly saturated or saturated ring(s)

5-Membered rings (Heteroatom N, O, S)

S

Thiophene

NH

Pyrrole

O

Thiophene

Other examples

N

NH

Imidazole

N

S

Thiazole

NH

Indole

NH

R'' NHR

R'R=HR'=CO2HR'''=H

Tryptophane

R=HR'=HR'''=OH

Serotonin R=AcR'=HR'''=OCH3

Melatonin

N

NH

N

N

NH2

Adenine(purine der.)

N

NH

H2N

R

R=CO2H: HistidineR=H: Histamine

N

S

N

NH3C

HO

H2N

CH3

Thiamin(Vit B1)

X X X X X XX: S, Se

e- in d-orb.

Cyclopentadienyl anion

Thiophene

S

Criteria for Aromaticity (Hückel)(Monocyclic) ringPlanarNo of π-electrons in conjugation 4n+2 (n: 0, 1, 2,....)

S

5-membered rings - electron rich - reactive i E-fil. Ar subst.

X+ E

XEH X

EH X

EH X E

X+ E

X

EH

X

EH

X E

React. in α-position generally preferredSelectivity not always goodReact.: Pyrrole > thiophene > furan

6-Membered rings (Heteroatom N)N

Pyridine

Other examples

N

Quinoline

NN

Pyrimidine

N N

Pyridazine

Rare in nature

N

N

Pyrazine

NNH

NH2

O

Cytosine

N

Quinine

H3CO

HO

N

N

Ant pheremoneN N

HydralazineAntihypertensive drug

H2NHN

NH

H H

H H

Pyridine as a base

N NH

+ H

NH

H H

H H

NH

H H

H H

H

pKa: 5.2

NH

pKa 0.4

NH

pKa 11.3

N

NH

pKa 7.1(≈amidine)

N

S

pKa 2.5

sp2 N less basic than sp3

Electrophilic Reaction on Carbon: E-phil. Ar. Subs.

6-membered rings - electron deficient - ↓ reactivity

N

NE

N

HE

N

E

+ E

+ res. forms

•Both C and N may react•3/5 pos. most reactive C•Diazines less reactive•Sulfonation, Nitration, halogenatil•Not FC react.

N NH

NH

H NO2

N

NO2H / NO2 H / NO2

+ res. formsBenzo ring most reactiveMuch slower react. than naphthalene

N N N N N

6-membered rings - electron deficient - reactive in Nu-fil. Ar subst.

N ClOMe

NOMe

Cl

+ res. form

N OMe

2 / 4 Pos. reactive; electron def. C, neg. charge partly on N in intermed3 / 5-Pos. much less reactive (benzenoid pos.)

Nucleophilic Aromatic Substitution

•SNAr

•SN1: Via arylic cation

•Benzyne

•SRN1: Involves radicals

•VNS: Vicarious nucl. Subst.

X Nu XNu

XNu

XNu

Nu

Nucleosides, Nucleotides, Nucleic acids (DNA; RNA)

DNA bases

DNA Nucleosides

2-Deoxyribosides

RNA bases

HN

N

O

O

Thymidine

N

N

NH2

O

Deoxycytosine Deoxyadenosine

N

N N

NNH2

HN

N N

NO

H2NO O O O

OH OH OH OH

HO HO HO HO

Deoxyguanoosine

HN

NH

O

O

Thymin

N

NH

NH2

O

Cytosin Adenine

N

N NH

NNH2

Guanine

HN

N NH

NO

H2NHN

NH

O

O

Uracil

Cytosin Adenine Guanine

RNA Nucleosides

Ribosides

HN

N

O

O

Urinine

Cytosine

Adenosine

O

OH

HO GuanoosineOH

Nucleotides

OO

XHO

B

P

OO

XO

B

P

OO

OHO

XO

B

OO

5'

3'

Double α-helix (DNA)A-T and G-C Base pairs

NN

O

O CH3

HN N

N HH

N

N

NN

O

N

N N

ON

N

H

NH

H

HH

DNA

Procaryotes and eucaryotes

5'

5'3'

3'

Leading strandLagging strand

3' 5'

5' 3'

3' 5'

3'5'

Replication

Transcription

DNA polymerase

DNA

5'

5'3'RNA polymerase

DNA

5'

5'3'

3'5'

(+) stranded RNA

Translation

mRNA(+) stranded RNA

3'5'

Protein

3'5'

3'5'

Nucleotide sequence in DNA - genetic information

DNA helicases: UnwindingDNA binding proteins: Prevents winding backDNA primase: formation of DNA/RNA primer (from free nucleosides in cell)DNA polymerase: Catalyse elongation of new strand (5’ - 3’)

Lagging strand:DNA ligase: Connects Okasaki fragments

OO

O

T

P

OO

O

C

P

OO

OO

5'

3'Template strand

O O

OH

G

P

O O

O

A

P

OO

OO

5'

3'

New strandOO

O

T

P

OO

O

C

P

OO

OO

5'

3'Template strand

O O

OH

G

P

O O

OH

A

P

OO

OO

5'

3'

New strand

Next nucleotideGuanosine triphosphate

OPO

OO

O

OO

3'

DNA

5'

5'3' RNA polymeraseDNA

5'

5'3'

(+) stranded RNA3'5'

Uracil instead of thymine

Transcription: DNA - RNA

Translation: RNA - Protein3 RNA bases coding for one AA (see Table 28.1)Protein synthesis occurs at ribosomes

mRNA(+) stranded RNA 5' 3'

50S

30S

Ribosom

Protein

NH3+

NH3+

CO2-

70S

initiator tRNA

OH 3'

tRNA-Met

O SO

NH2

tRNA-fMet

O SO

HNO

mRNA30S ribosoe

O SO

HNO

3'mRNA

5'

30S initiator complex

AUG

50S ribosome

3'5' AUGU A C U A C AU C

U A C

O SO

HNO

U A C

Anticodon

Codon

3'

5'

fMet

U A C

A U G C G A G C U

3'

5'

fMet

U A C

A U G C G A G C U

Arg

G C U

3'

5' A U G C G A G C U

A-site

Arg

G C U

fMetRibosomewithP-site and A-site

3'

5'

U A C

A U G C G A G C U

Arg

G C U

fMet

3'

5'

fMet

U A C

A U G C G A G C U

Arg

G C U

3'

5'

U A C

A U G C G A G C U

Arg

G C U

fMet

O SO

HNO

fMet

OHN

O

NH2Arg

NH

NH2 OH O

ONH

HN O

O

S

NH

NH2HN

Formyl groupProtection of N-terminal

DNA / RNA Synthesis: Protecting groups and activating groups (cf. peptide synth)

OO

O

B

P

OO

O

B

OO

O

OO

HO

B

P

OHO

O

B

OON

NH3 / H2O[ox]

OO

O

B

P

OO

O

B

O

O

N

Phosphite Phosphate

acidcatalyst

OHO

O

BP

OO

O

B

O

O

NN

PO

O N

Phosphoramidite

The Polymerase Chain Reaction (PCR, 1986)technique for quickly "cloning”(make many copies of) a particular piece of DNA in the test tube (rather than in living cells like E. coli).

primers: short oligonucleotides (ca 20 nucleotides) precisely complementary to the sequence at the 3' end of each strand of the DNA

DNA

5'

5'3'

3'

95 oC(denaturation)

5'

5'3'

3'

Addition of primers

5'

5'3'

3'

Taq polymeraseMg2+

Nucleoside-triphosphates

5'

5'3'

3'

Repeat cycle

4 copies

Repeat cycle

16 copies

ca 1011 copies in a few hours

Tac DNA polymerase: Heat stable enzymefrom Thermus aquaticus (bacteria)in hot springs Yellowstone Nat. Park

Lipids (McM chapt 27)Naturally occuring, lipophilic comp.

•Wax, fat oils•Soaps•Phopholipids•Prostaglandins•Terpenoids•Stereoids

Wax, fat, oils: Derivatives of fatty acids (carboxylic acids)

O

OH

Ex saturated fatty acid: Stearic acid (C18)

O

OH

Ex unsaturated fatty acid: oleic acid (C18)

O

OH

linoleic acid (C18)

ΩΩ-6

Wax: esters between fatty acid and long chain alchohol

Fat (solid), oil (liquid) - Soaps

Basic ester hydrol. - Saponifications

O

O Na

Hydrophilic headLipophilic tail

Ca 2+ - “Hard water” Ca(OCOR)2 (s)

Cationic soaps

O

O

OR

OR''

Triglycerides

NaOH (aq) OH

OH

OR

OR''

OR'

Glycerol

O

O

ONa

Na

Na

Soaps

HOOO

R'

Phospholipids

Extracellular fluid

Intracellular fluid

Cell membranePassive diffusion: Small, lipophilic

O

O

OR

PO

Glycerophospholipids

OO

R'

R: saturated

R': unsatur.O

O (CH2)2NR3

R: H, Me

Diester Phosphoric acid

O PO

OO

R'O

O (CH2)2NR3

OO

R

Hydrophilic head

2 Lipophilic tails

Sphingomyelins

OHNH2OH

(CH2)12CH3

Sphingosine

O

NHCO(CH2)nCH3

OH

(CH2)12CH3

n: 16-24

PO

(CH2)2NH2R3O

coating of nerve fibers

Prostaglandins etc

Subtypes COXCOX-1: Synth of essential prostagland.COX-2: Active only under inflamations

CO2H158

11 1420

Arachidonic acid

Cyclooksygenase(COX)5

15CO2H

O O

Prostglandin H2(PGH2)

Tromboxanes

Prostaglandines

Prostasyklines

Many different biolog. effectsInflamations, allergy responce

Inhib. by many pain killers

RofecoxibVioxx®

Avreg 2004

COX2/COX2: 35

SO

O

OO

COX2 inhibitorsCoxibes

Prostaglandins etc

Subtypes COXCOX-1: Synth of essential prostagland.COX-2: Active only under inflamations

CO2H158

11 1420

Arachidonic acid

Cyclooksygenase(COX)5

15CO2H

O O

Prostglandin H2(PGH2)

Tromboxanes

Prostaglandines

Prostasyklines

Many different biolog. effectsInflamations, allergy responce

Inhib. by many pain killers

RofecoxibVioxx®

Avreg 2004

COX2/COX2: 35

SO

O

OO

COX2 inhibitorsCoxibes

Terpenoids

O

Isopentenylpyrophosphate

(C-5)

P PO P PO

P

OOH

3 ATPOH

HO

OHOMevalonate(C-6)

N

N N

NNH2

OO

OHHO

PO

OHOP

O

OHOP

O

OHHO

ATP, Adenosine-5'-triphosphateP

C-10: MonoterpenesC-15: SesquiterpenesC-20: DiterpenesC-25: SesterterpenesC-30: Triterpenes

O

(+) Camphor α-Pinene β-Pinene

O

Isopentenylpyrophosphate

(C-5)

P PRearrange

O

Dimethylallylpyrophosphate

(C-5)

P P O P PH

O

trans-Geranylpyrophosphate

(C-10)

P P

OH

trans-Geraniol

OH

(-)−β-citronellol (-) Linalool

OH

OH(+)-α-Terpineol (-)-Menthol

HO

(+)-Carvone

O

OH

Thymol

O

trans, trans-Farnesylpyrophosphate(C-15)

P P OPP+

tail to tail coupling

Squalene (C-30)

O

HO

Lanosterol

H

Squaleneepoxidase

Enzyme-Nu

H

HO H

H

Enz--Nu

H

Squalene epoxide cyclase

H

B All stereoids

Stereoids

A B

C D1

2

34

5 678

910

1112

13

14 15

16

17 17β 17α

B / C og C / D always trans

10β

5α

A / B trans fused

10β

A / B cis fused

5α

Sex Hormones

H

HHO

Testosterone

OH

5α-reduktase H

HHO

5α-Dihydrotestosterone (5DHT)More active A-B ring transCis isomer inaktive

OH

H

H

HHOProgesterone

O

Many semisynth drugs in use (better bioavalabil.)

HO

H

HH

O

Estrone

in vivo

HO

H

HH

Estradiol

OH

HO

H

HH

Estriol

OH

in vivo

(low activity)

(fast metabol)

OH

(low activity)

Used in drugs

HO

H

HH

OH

H K2 ekviv.

Ethinyl estradiol(only estrogen im P-pills)

Estrogens

Corticostereoids

Mineralcorticoid

O

H

H H

OOH O

OH

AldosteroneRegulation of elektrolyttic ballanceincrease re-uptake of Na (and hence H20)

GlucocorticoidH

H H

O

O

OH

HO OH

Hydrokortison

Effect on metabolism (karbohydrates, lipids, proteins)Antiinflammatoric

Numerous semisynth. analogs as drugsVarious antiinflam. activity, mineralcorticoid side effects