protein synthesis inhibitors & their chemistry
TRANSCRIPT
Protein Synthesis Inhibitors &
Their Chemistry
Dr. Aisyah Saad FAR241
September 2015
1
antibiotics during protein synthesis?where& which
Note: Eukaryotic ribosomes consist of 60S and 40S subunits, making up 80S ribosomes
❄
❄
❄
❄
❄
2
O
O
O
OHHOHO
O
O
OOH
(H3C)N
O OH
OMe
Macrolides
2
Amphenicols HN
O
Cl
Cl
OH
OH
CH3
O 1
NO
HN
HO
OOHSMe
HO
HO
Lincomycin
3OH O OH O
OH
NH2
O
NHO
OH
Tetracycline4
Protein Synthesis Inhibitors
OH2NNH2R1
O
H2NO
HO
O
MeHNCH3
HO
NH2
OH
R2
Aminoglycosides
5
3
Think-Pair-ShareWhich antibiotic(s) is/are NOT a glycoside?
4
AmphenicolsHN
O
Cl
Cl
OH
OH
CH3
O15
HO
HN
OH
Y
OX
H
H
a General structure
Amph
enico
ls
6
Amph
enico
ls
chloramphenicol
thiamphenicol
cetophenicol
N+
OHHN
OHO
Cl
Cl
O
-O
HN
O
Cl
Cl
OH
OH
SO
O
HN
O
Cl
Cl
OH
OH
CH3
O
7
Chloramphenicol
N+
OHHN
OHO
Cl
Cl
O
-O
Naturally occurring compoundFour possible isomers Only D-threo-chloramphenicol is active (1R, 2R)Serious adverse effect: dose-related aplastic anaemiaThus, last resort in anti-infective therapyAm
phen
icols
8
N+
OHHN
OHO
Cl
Cl
O
-O
Chloramphenicol binding sites
Binds to 50S ribosomes
Bacteriostatic
9
Chloramphenicol Resistance
N+
OHHN
OHO
Cl
Cl
O
-O
but, enzyme-mediated resistance exploits this e.g.dehydrogenation, nitro group reductionacetylation e.g. bacterial chloramphenicol acetyltransferases-- acetylates the hydroxyl group 3-acetoxychloramphenicol →1,3-diacetoxychloramphenicol
all the functional groups are important for activity
replace nitro
with other EWG
s:
activity drops
.
10
Think-Pair-ShareCan you predict the major biotransformation pathway of chloramphenicol?
11
Macrolides2 O
O
O
OHHOHO
O
O
OOH
(H3C)N
O OH
OMe
12
O
O
O
OHHOHO
O
O
OOH
(H3C)N
O OH
OMe1
10
13
3'Erythromycin binding sitesBinds to 50S ribosomes
13
Erythromycin A
O
O
O
OHHOHO
O
O
OOH
(H3C)N
O OH
OMe1
10
13
3'Cladinose
Desosamine
derived from certains strains of Streptomyces erthreus
Erythromycin C=3’-OH
active vs some G+; not Enterobacteriaceae
numbering?
pH-dependent activityincreases up to pH 8.5 (optimum)pH 7, loses 14% activity (after 24 hours)
In weak acid: activity decreases (in few hours)–why??
Erythromycin B=no 13-OH
14
This ketal form of Erythromycinalso causes GI crampingAc
id Se
nsiti
vity
Acid-catalysed
Clinically important reactions
pH ~2.5-4.0
In weak acid Erythralosamine(-desosamine, -2H2O)
13 7
10
15
O
O
O
OHHOHO
O
O
OOH
(H3C)N
O OH
OMe1
10
13
3'
OMeClarithromycin
Erythromycins
Clarithromycin
How to avoid the ketal formation ?
1.
2. Increase ring size, up to 16-membered ring.E.g. ??
Mac
rolid
es
3. ??
Ketal formation is reduced thus,1. Less cramping2. More lipophilic, better plasma level cf Ethromycins
16
Lincomycin3 NO
HN
HO
OOHSMe
HO
HO
17
LincomycinsN
O
HN
HO
OOHSMe
HO
HO
LincomycinN
O
HN OOHSMe
HO
HO
ClClindamycin
Lincomycin is isolated from Streptomyces lincolnesis Sugar component : methyl α-thiolincosaminide (a rare 8C-sugar) Clindamycin : semi-synthetic derivative Reserved for penicillin-resistant G+ d/t:1. Pseudomembranous colitis (caus. Clostridium difficile)2. Stevens-Johnson syndrome
18
NO
HN OOHSMe
HO
HO
Cl
Clindamycin binding sites
Inhibits 50S ribosome
With Cl, it is more bioactive and lipophilic than lincomycin.
19
NO
HN OOHSMe
HO
HO
ClN
O
HN OOH
OH
HO
HO
ClpH 0-4
NCOOH
H2N OOH
HO
HO
Cl
HSMe
SMe
pH 9
pH 9
NO
HN OOHSMe
HO
HO
HO
2✼
Acid
Sens
itivit
y Clindamycin
3✼1✼
20
Tetracycline4 OH O OH O
OH
NH2
O
NHO
OH
21
OH O OH O
OH
NH2
O
NHO
OH
wide spectrum of activity binds to 30S subunit of bacterial ribosomes a bacteriostatic antibiotic
Tetracyclines
22
Naphthacene
12
3
4567
8
9
10 11 1212a
5a
ABCD
1,4,4a,5,5a,6,11,12a-octahydronaphthacene
23
Tetracycline
OH O OH O
OH
NH2
O
NHO
OH
12
3
4567
8
9
10 11 1212a
5a
ABCD
24
TetracyclinesOH O OH O
OH
NH2
O
NHO
OH
Chemistry
25
OH O OH O
OH
NH2
O
NHO
OH 1 2121110
34D C B A
C1,2,3,4 : Vinylogous α-amino ketone group; the dimethylamino group can be easily liberated
C1-12a : α-ketol group with a tertiary carbinol function - blocks enolization
B-C-D rings : a chromophore consisting a phenol and β-diketone structure. Visually yellow. Ring A : another chromophoreSensitive to light : due to A & BCD
A trivalent acid. Low aqueous stability. Epimerizes and chelates readily.
TetracyclinesAmphoteric in nature.Has 3 pKa values at different parts of its structure
26
Tetracycline shows acidic nature with pKa1 = 2.8 - 3.4 where enolization in Ring A tends to take place.
O
O
O
NH2
O
OH
O
NH2H
OH-
O
O
O
NH2
Tricarbonyl Framework
AAA
Tetracyclinesacidic H
Guide to pKa HBr, pKa = -9.0; Acetic acid, 4.76; Water, 15.7, CH3, 50
27
BBCD BCD
Almost neutral pKa = 7.2 - 7.8where enolization in Ring BCD occurs
β-dicarbonyl system
-H OOOH OHOOH
OH- OOOH
CD
Tetracyclines“Phenolic enone system”
28
pKa = 9.2 - 9.7
OHO
NH2
O
OHNH
OH-OH
O
NH2
O
OHN
AA
Tetracyclines
Tetracycline is amphoteric. It is sold as Na or Cl salts.
29
BB Extremely important occurs between pH 2 - 6 favoured in buffered solutions, which leads to an equilibrium consisting 2/3 tetracycline & 1/3 epitetracycline Epitetracycline is 1.5% of tetracycline Take extra, extra care when you’re asked to prepare an solution of tetracycline
EpimerizationOH
O
NH2
O
OHN H
OHOH
NH2
O
ON H
A A
BB
Epitetracycline
OHOH
NH2
O
OHN
OHO
NH2
O
OHNH
AA
Tetracyclines
*Chemistry important to formulation
30
Tetracyclines
*Chemistry important to formulation
OH O O
CH3HO
121110
D C
OH O O
H3C
O
isotetracycline
Under basic conditions:
31
OH O O O
OH
NH2
O
NHO
OH
OHOOO
HO
H2N
O
N OH
OH
M
Chelation with Di- & Trivalent Metal ions: the complex formed
Are not active, and not absorbedfrom GIT
*Clinically important chemistry
32
TetracyclinesOH O OH O
OH
NH
O
N
OH10
7 6
R2 R3R1 R4
R521
5
12
Changes on these substituents have little detrimental effects on
activity
❄❄
❄ C4 & C5a must maintain the right configuration
Phenolic enone system The principal functional framework; Chelation
SummaryTrione framework. Weak
acid; involves in epimerization
Chelation
33
5Aminoglycosides534
Streptomycin
Neomycin B
Kanamycins
GentamicinOO
H2N
O
HOOH
NH2
H2N
O
O
HO
OH
NH2
OH
O
HOOHH2N
H2N
O
HONHMe
O
HOHO
OOHC
HOCH3
OOH
HONH
H2N
HNOH
NH
NHH2N
OHO OHOH
NH2O
H2NO
HO
OH2N
HO
NH2
OH
OH
OH2NNH2CH3
O
H2NO
HO
O
MeHNCH3
HO
NH2
OH
CH3
fam
ily
Aminoglycosidessourced from strains of Streptomyces and Micromonospora.binds to 30S subunit of bacterial ribosomes.
35
Terminology A glycoside is...
a glycosideaglycone
glucose
OHO
HO
OH
OHOH
OH
HO
HO
OHOH
HO
Some medicinally-important monosaccharides
OHO
HO
OH
OHOH
D-Glucose
OH
HO OH
OHO
D-Ribose
O
HOHO
OHOH
OHD-Mannose
O
H2NHO
OH
OHOH
3-amino-3-deoxy-D-glucose
Aminoglycosides
OH
HOO
HO
OHO
HO
OH
OH
OH
OH
36
Amino alcohol of Aminoglycosides(Aglycones)
OHHO
HOHO
OHOH
OHHO
HOHO
OHNH2
Streptidine
2-deoxystreptamine
Streptaminescyllo-inosite
OHHO
HOHN
OHNH
NH
H2N
NHH2N
HOHO
H2NOHNH2
37
1O
HO
OHNH
NH2
NHHO
HN
HN
NH2
S1S2
1
3
6
Streptomycin
OO
H2N
NH2OH
S1
S2
S3
13
4
52Neomycin
OH2NO
HO
NH2
S1S2
1 3
4
6
Kanamycin/Gentamicin
3
Aminoglycosides
38
O
HO
OHNH
NH2
NHHO
HN
HN
NH2
S1S2
1
3
6
Streptomycin
OHHO
HOHO
OHOH
OHHO
HOHO
OHNH2
Streptamine
39
Streptomycin
Streptidine
L-streptose
N-methyl-L-glucosamineO
HONHMe
O
HOHO
OOHC
HOCH3
OOH
HONH
H2N
HNOH
NH
NHH2NO
HO
OHNH
NH2
NHHO
HN
HN
NH2
S1S2
1
3
6
the nucleus streptidine is linked to other sugars a front-line drug against M. tuberculosis in combination with other drugs exhibits ototoxicity rapid resistance
40
Neomycin
OO
H2N
NH2OH
S1
S2
S3
13
4
5
41
OO
H2N
O
HOOH
NH2
H2N
O
O
HO
OH
NH2
OH
O
HOOHH2N
H2ND-ribose
D-neosamine
2-deoxystreptamine
L-neosamine B❄
Epimer at ❄ is Neomycin C
poor GIT absorption when orally administered. so, found its way in topical applications e.g. eye drops & creams Framycetin =
Neomycin B + C
Neomycin B
OO
H2N
NH2OH
S1
S2
S3
13
4
5
42
Kanamycin/Gentamicin
OH2NO
HO
NH2
S1S2
1 3
4
6
43
2-deoxystreptamine3-amino-3-deoxy-D-glucose 6-amino-6-deoxy-D-glucose
Kanamycin A: R = OHKanamycin B: R = NH2
Kanamycin a complex of three antibiotics i.e. Kanamycin A, B & C. potent against Gram +ve (including penicillin-resistant streptococci) & Gram -ve bacteria. a second-line drug in tuberculosis treatment.
OR OHOH
NH2O
H2NO
HO
OH2N
HO
NH2
OH
OH
44
Kanamycin
Also called ‘Nebramycin Factor 6’
Less susceptible to enzymatic degradation due to the lack of 3-OH of the 2-amino sugar
Slightly more active towards Ps. aeruginosa than Gentamicin
Inactivating enzymes catalyse biochemical reactions e.g. O-phosphorylations, O-adenylation, N-acylation
Stability towards inactivating enzymes is conferred by the 4-amino-2-hydroxybutyl group
Treatment of serious Gram -ve infections which are not responsive to Gentamicin.
Amikacin
OHO OHOH
NH2O
HNO
HO
OH2N
HO
NH2
OH
OH
H2N
O
HO
OH2N OHNH2
OOHO
OH2N
HO
NH2
OH
OH
H2N
Tobramycin
Analogues of
45
2-deoxystreptamineL-garosamine D-purpurosamine
Gentamicin C1 ; R1 = CH3 R2 = CH3
Gentamicin C1α; R1 = H, R2 = H Gentamicin C2 ; R1 = CH3, R2 = H
OH2NNH2R1
O
H2NO
HO
O
MeHNCH3
HO
NH2
OH
R2
isolated from Micromonospora purpurea a mixture of three components i.e. Gentamicin C1, C1α & C2 active against Gram +ve & -ve plus some Ps. aeruginosa strains co-administered with carbenicillin to delay onset of resistance
Gentamicin
46
Summary
How do they look like?
How does their structures affect how they work/act?
O
HONHMe
O
HOHO
OOHC
HOCH3
OOH
HONH
H2N
HNOH
NH
NHH2N
Aminoglycosides
47
O
O
O
OHHOHO
O
O
OOH
(H3C)N
O OH
OMe
Macrolides
2Amphenicols H
N
O
Cl
Cl
OH
OH
CH3
O 1
NO
HN
HO
OOHSMe
HO
HO
Lincomycin
3OH O OH O
OH
NH2
O
NHO
OH
Tetracycline4
Chemistry Protein Synthesis Inhibitors
OH2NNH2R1
O
H2NO
HO
O
MeHNCH3
HO
NH2
OH
R2
Aminoglycosides
5
48