NOSH ASPIRIN
Aspirin
COX-1COX-2
Reduced mucosalBlood flow
Impaired platelet aggregation
Impaired defence
Epithelial damage
Acid back diffusion
Impaired platelet aggregation
Impaired mucosal repair
Mucosal injury and bleeding
Leukocyte adherence
Leukocyte activation
NO NO
NONO
NO
HS HS
HS
HS HS
Nosh- aspirin
Super-aspirin New hybrid, aspirin as the scaffold Active part of both NO & HS-Aspirin Release both NO & H₂S 15,000 times more potent than NO-Aspirin 80 times more potent than HS-Aspirin
Nosh-aspirin
(4-(3-thioxo-3H-1,2-dithiol-5-yl) phenyl 2-((4-(nitrooxy)-butanoyl)oxy) benzoate)
(4-(nitrooxy)butyl (2-((4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy)carbonyl)phenyl))
(4-carbamothioylphenyl 2-((4-(nitrooxy)butanoyl)-oxy)benzoate)
(4-(nitrooxy)butyl 2-(5-((R )-1,2-dithiolan-3-yl)pentanoyloxy)-enzoate)
11 human cancer cell lines of 6 different histological subtypes
Colon
Breast
Pancreas
Prostate
Lung
T cell leukemia
HT-29,HCT-15,SW140
LNCaP
A549
MCF7,MDA MB-231,SKBR3
BXPC3,MIAPaCa-2
Potency of nosh compounds
Nosh compounds IC₅₀ Value
NOSH-1
NOSH-2
NOSH-3
NOSH-4
70-120nm
4300-7500nm
240-800nm
48-280 nm
( IC₅₀ -Conc. of an inhibitor(cell growth inhibition) where response is reduced by half)
24 hrs.
In vitro
100000 250000
72 hrs.
HT-29 human colon cancer cells
Nosh-1 aspirin
NOSH-2 NOSH-3 NOSH-4
>60,000 >600 >16,000
Human colon cancer in mouse
Cancer cells to self-destructInhibited proliferation of cellsNo toxicity to normal cellsCould be used in conjunction with other drugs
Evaluation of nosh-1 toxicity
LDH release as a level of cellular toxicity
Cells were treated with several conc.of NOSH-1
Compared with untreated controls
Dose and time depandent
Toxicity profile nosh-1 as measured by LDH release in HT-29 colon cancer cells
Remarkable degree of safety
Carragenan rat paw edema model
Compare COX-dependent anti-inflammatory
activity of ASA to that of NOSH-1
Animals receiving vehicle showed a fast
time-dependent increase in paw volume
Animals receiving ASA showed a weak inflammation
Anti-inflammatory effect of NOSH-1 was dose depandent
Vehicle ASA NOSH-1 NOSH-10
20
40
60
80
100
PGE2Levels pg/mg protein
0.21
0.520.56
mmol/kg
PGE2 content of paw exudate- control,ASA,nosh-1
Conclusion
Research and development phase
Preclinical studies
Research is in progress for efficacy and safety issues
Drawback
NO-Aspirin HS-Aspirin
Quinone methide intermediates High IC50s for cell growth inhibition
High IC50s for cell growth inhibition
IC₅₀ -Conc. Of an inhibitor(cell growth inhibition) where response is reduced by half
Problems
Too acidic, can cause stomach ulceration Haemorrhagic stroke Reye’s syndrome Renal failure
Aspirin(Acetylsalisylic acid)
Worlds leading OTC pain reliever
Inexpensive
Prevents PG by inhibiting cyclo-oxygenase
Analgesic, antipyretic and antiinflammatory,
antiplatelet activity
Additional- R.A, reduce cancers
Buffered aspirin
Aspirin is “buffered” with various bases
MgCO3, Mg(OH)2, Al(OH)3, etc.
Increases pH so acidity is reduced
Increases absorption into blood stream
NO NSAID
Dilate blood vessels Increases mucosal flow Prevents G.I bleeding Increase analgesic and anti- inflammatory potency
Reduced gastric injury –confirmed in human studies
HS NSAID
Potent anti-inflammatory Prevent leukocyte adherencePrevent G.I bleeding
• The effect of the hybrid was also far greater than the sum of its parts. Its potency was as much as 15,000 times greater than existing NO-aspirins and 80-fold more than those that incorporate H2S. The upshot is that a drug based on this hybrid would require lower doses to be effective, minimizing or potentially eliminating its side effects.
NO-NSAID
Dilate blood vessels Prevents G.I bleeding Drawback: quinone methide
intermediates High IC50s for cell
growth inhibition
HS-NSAID
Potent anti-inflammatory activity
Drawback: relatively high IC50s for
cell growth inhibition
• IC₅₀ -Conc. Of an inhibitor(cell growth inhibition) where response is reduced by half
Synthesis of aspirin