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Alkaloids
Medical Chemistry
Lecture 8
2007 (J.S.)
Heterocyclic compounds
are organic compounds that contain rings composed of
carbon and other atoms heteroatoms in natural
heterocycles mostly nitrogen, sulfur, and oxygen.
Heterocycles exist as three-, four-, five-, six-, and multi-membered rings.
N
H
N
N
H
N
N
N
H
thiofene
thiolane
N
H
quinoline
N
N
purine
N
H
furan
tetrahydrofuran
indole
isoquinoline
N
N
pteridine
chroman
N
4
Nomenclature of heterocycles
Common names for many ring systems are accepted by
the IUPAC rules:
rings with maximum double bonds
furan, pyrrole, indole, pyridine, etc.
saturated ring systems
either prefixes dihydro-, tetrahydro-, perhydro-,
or in five-membered rings pyrroline, pyrrolidine,
in six-membered rings piperidine, piperazine.
N
N
H
pyrrole
N
H
pyrroline
N
pyridine
N
H
pyrrolidine
N
H
piperidine
N
H
imidazole
HN
N
H
imidazolidine
ditri-
Saturated
Unsaturated
Number of
Heteroatom
nitrogenous oxygenous
ring members
sulfurous
azthiox-
3
4
5
6
-irine, -irene
-ete
-irane
-etidine
-irine
-etane ..
-epine
-ocine
-epane
-ocane
-epane
..
Pyrrole
is not a base:
Imidazole
is a weak base;
One of the two nitrogen
atoms can add proton:
N+
H
The unshared electron pair of
nitrogen is not able to add proton.
N
H
+
NH
N
H
+ H+
N
H
Pyrrole
N
H
CH2
Cyclic tetrapyrroles
CH3
CH2
CH3
NH
N
N
HN
CH3
porphin
N
H
HN
CH3
COOH
COOH
NH
corrin
protoporphyrin IX
Linear tetrapyrroles
CH3
N
H
N
H
N
H
N
H
CH2
N
H
HOOC
COOH
CH3
CH3 CH3
N
H
bilirubin
N
H
CH2
N
H
Coenzyme B12
(cobamide cofactors 5-deoxyadenosylcobalamin, methylcobalamin)
methylcobalamin
5-deoxyadenosylcobalamin
CH3
N
Co
N
N
+H
pyrrolidine
+
N
HH
pyrrolidinium ion
N
H
COOH
proline
(pyrrolidine-2-carboxylic acid)
N
COOH
H
4-hydroxyproline
5-Oxoproline (lactam of
glutamic acid) is formed
in the group translocation
of amino acids (-glutamyl
cycle).
HO
N
COOH
H
5-oxoproline
(pyroglutamate)
10
Indole
(2,3-benzopyrrole)
CH2-CHCOOH
N
H
NH2
N
H
tryptophan
serotonin
CH2-CH2
NH2
N
H
CH3-O
CH2-CH2
NHCO-CH3 O
N
H
melatonin
N
H
indole-5,6-quinone
11
O
N
H
imidazole
+ H+
N
H
imidazolium cation
CH2-CHCOOH
NH2
N
H
histidine
The side chains of histidyl residues are responsible for the buffering ability
of proteins at physiological pH values, because only the imidazolyl groups
(pKB 8.0) can take part in protolytic reactions under those conditions.
Histamine originates by decarboxylation of histidine
and acts as a vasodilator in inflammations and
N
allergic reactions. It also causes contraction of
smooth muscles of the bronchial stem and the
N
acidic stomach secretion.
H
CH2-CH2-NH2
histamine
12
Thiazole
N
CH3
N
N
CH2-CH2OH
S
NH2
COOH
O
RCO-NH
N
S
CH3
CH3
N-acylaminopenicillanic acid
13
S
thiolane
thiophene
O
HN
NH
C N
carboxybiotin
NH
COOH
S
lipoic acid (an oxidant)
COOH
+ 2H
- 2H
SH
SH
14
Furan
O
O
furan
tetrahydrofuran
Pyran
OH
OH
OH
D-ribofuranose
O
4H-pyran
O
4-pyranone
OH
tetrahydropyran
H
OH
OH
(-pyrone)
OH
D-ribopyranose
15
Many plant substances comprise the pyran ring that is usually fused
O
condensed with the benzene ring:
Those structures appear, e.g., in
flavonoids, in the active component
of hemp tetrahydrocannabinol (THC),
tocopherols, and derivatives of coumarin.
chroman
chromone
HO
CH3
CH3
CH3
O CH
3
CH3
CH33
CH3
coumarin
(2-hydroxycinnamic lactone)
16
+ H+
N
N+
pyridinium H
pyridine
O
C
OH
nicotinamide
NH2
N
CH3
alkaloid nicotine
HO
H3C
CH2OH
CH2OH
N
pyridoxal
HO
H3C
CH=O
CH2OH
N
pyridoxamine
HO
H3C
CH2-NH2
CH2OH
N
17
CONH2
anhydride bond
O
N
CH2OPOPOCH2
adenine
OH OH
OH HO
OH
O-(H or PO32)
H H
CONH2
CONH2
Oxidized form NAD+
(aromatic ring, positive charge)
+ H+
18
Pyridoxal phosphate
CH2OH
HO
CH2OH
H-C
HO
O
CH2OPO
O
H3C
H3 C
pyridoxal phosphate
19
Pyrimidine
(1,3-diazine)
is a dibasic compound.
N
N
OH
N
HO
OH
N
HO
cytosine
HO
N
uracil
N
thymine
2,4-dihydroxypyrimidine
4-amino-2-hydroxypyrimidine
CH3
5-methyluracil
They exist in two tautomeric forms. Only the lactam forms can be
ribosylated to give nucleosides:
O
OH
lactim form
HO
HN
N
N
N
H
20
Purine
(pyrimidinoimidazole)
6
1
NH2
N
H
N
H
adenine
N
N
H
hypoxanthine
6-hydroxypurine
HO
N
xanthine
N
H
HO
OH
N
H
2,6-dihydroxypurine
OH
OH
N
N
H
ammonium hydrogen urate
O NH4+
N
2-amino-6-hydroxypurine
OH
N
N
H
N
guanine
OH
HO
H2N
6-aminopurine
OH
atypical numbering!
N7
OH
HO
OH
N
H
lactim form
21
caffeine
theophylline
theobromine
1,3,7-trimethyxanthine
1,3-dimethylxanthine
1,7-dimethylxanthine
SH
N
N
N
H
allopurinol
N
N
N
H
mercaptopurine
22
Pteridine
(pyrimidinopyrazine)
3N
2
a N
1
N
N
Tetrahydrobiopterin (BH4)
acts as the reducing coenzyme in certain hydroxylations catalyzed
by monooxygenases. It supplies two atoms of hydrogen and is
oxidized to the quinoid form of dihydropterin:
O
HN
H-NH
H
CHCHCH3
2H
OH OH
N
H
tetrahydrobiopterin (BH4)
reduced form
HN
HN
CHCHCH3
OH OH
N
H
dihydrobiopterin (qBH2)
oxidized (quinoid) form
23
N
H2N
CH2-NH
CONH-CH-CH2-CH2-COOH
glutamate
2-amino-4-hydroxypteridine CH2
Tetrahydrofolate
p-aminobenzoate
(n = 1 5)
pteroic acid
N
5
CH2-NH
10
CO-
Methotrexate (4-amino-10-methylfolate)
and aminopterin (4-aminofolate) are
antifolate drugs used as cytostatics in
oncology.
24
N
N
O
N
HN
O
benzo[g]pteridine
3
2
isoalloxazine
N
H
10
N
N
1
N
9
6
7
8
HN
O
CH3
N
CH2
CH3
HCOH
HCOH
HCOH
CH2OH
H3C
HN
H3O
C
O
NH
CH3
OCH3
coenzyme FAD
(oxidized form)
CH2
CH OH
NH2
CH OH
CH OH
CH2
N
O
O P O P O CH2
OH
O
N
OH
O
HN
O
CH3
N
CH2
CH3
OH
+2 H
OH
2H
HCOH
oxidized form
FAD or FMN
reduced form
FADH2 or FMNH2
26
CH2CH2CH2N
H
N
phenothiazine
chloropromazine
Cl
CH3
CH3
Tranquilizers
(neuroleptics, psychostatics)
Antidepressants
CH3
(thymoleptics, psychostimulants)
CH2CH2CH2N
N
N
CH3
CH3
dibenzothiepine
dosulepine
benzo[f]diazepine
dihydrodibenz[b,f]azepine imipramine
CH-CH2CH2N
Cl
diazepam (Valium)
CH3
CH3
27
Alkaloids
Alkaloids are
natural nitrogenous bases originating from amino acids
(sometimes called "secondary" metabolites),
occurring mostly in higher plants;
most of them are heterocyclic compounds,
they exhibit extraordinary variety of structural features,
many of them have marked biological effects
(quite a number of them possess curative properties).
It is not yet known, whether alkaloids are unwanted by-products or
products of detoxification, protective or reserve compounds, or useful
regulators.
pKB
Alkaloid
pKB
Atropine
Ephedrine
Quinine
Cocaine
4.35
4.64
5.07; 9.70
5.59
Nicotine
Morphine
Papaverine
Caffeine
6.16; 10.96
6.13
8.00
13.40
+ H+X
+ OH
R X
salt
(soluble
29
H
CH
C H3 O
nicotine
(vasoconstrictor, stimulant)
HO
quinine
(antimalarial)
quinidine
(antiarrhytmic)
HO
CH3 O
CH3 O
morphine
(narcotic action)
codeine (3-O-methylmorphine,
antitussic action)
C H2
CH3 O
C H3
CH
OH
HO
CH3
CH2
OCH3
papaverine
OCH3
(antispasmodic action)
30
CH3
CH3N
C OCH3
CH3 N
O C
O
O CO CH-CH2-OH
atropine
8-methyl-8-azabicyklo[3,2,1]octane (antispasmodic action)
tropane
cocaine
(local anaesthetic,
psychostimulant)
O
COOH
HN
CNHCH
H
CH2-CH3
CH3
CH3
lysergic acid
CH2-OH
methylergometrine
(uterotonic)
31