NOSH ASPIRIN

Aspirin
COX-1 COX-2
Epithelial damage NO HS Acid back diffusion Leukocyte adherence Impaired Impaired platelet mucosal repair aggregation Impaired platelet HS Leukocyte activation aggregation NO NO HS

NO HS

Reduced mucosal Blood flow

Impaired defence
NO

HS

Mucosal injury and bleeding

Nosh- aspirin
Super-aspirin New hybrid, aspirin as the scaffold Active part of both NO & HS-Aspirin Release both NO & HS 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-1,2dithiol-5-yl)phenoxy)carbonyl)phenyl))

(4-carbamothioylphenyl 2-((4(nitrooxy)butanoyl)-oxy)benzoate)

(4-(nitrooxy)butyl 2-(5-((R )-1,2dithiolan-3-yl)pentanoyloxy)-enzoate)

11 human cancer cell lines of 6 different histological subtypes

Colon Breast Pancreas Prostate HT-29,HCT15,SW140

MCF7,MDA MB-231,SKBR3
BXPC3,MIAPaC a-2 LNCaP

Lung
T cell leukemia

A549

Potency of nosh compounds

Nosh compounds
NOSH-1
NOSH-2

IC Value
48-280 nm
70-120nm

NOSH-3

4300-7500nm

NOSH-4

240-800nm

( IC -Conc. of an inhibitor(cell growth inhibition) where response is reduced by half)

Nosh-1 aspirin
In vitro
HT-29 human colon cancer cells

24 hrs.

72 hrs.

100000

250000

NOSH-2

NOSH-3

NOSH-4

>60,000

>600

>16,000

Human colon cancer in mouse

Cancer cells to self-destruct Inhibited proliferation of cells No toxicity to normal cells Could 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

Remarkable degree of safety

Toxicity profile nosh-1 as measured by LDH release in HT-29 colon cancer cells

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

PGE2 content of paw exudate- control,ASA,nosh-1

PGE2Levels pg/mg protein

100
80

60
40

0.21

20
0

0.56
Vehicle ASA

NOSH-1

NOSH-1

mmol/kg

0.52

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

IC -Conc. Of an inhibitor(cell growth inhibition) where response is reduced by half

Problems
Too acidic, can cause stomach ulceration Haemorrhagic stroke Reyes 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 antiinflammatory potency

Reduced gastric injury confirmed in human studies

HS NSAID

Potent anti-inflammatory Prevent leukocyte adherence Prevent 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

HS-NSAID

Dilate blood vessels Prevents G.I bleeding Drawback: quinone methide intermediates High IC50s for cell growth inhibition

Potent anti-inflammatory activity Drawback: relatively high IC50s for cell growth inhibition

IC -Conc. Of an inhibitor(cell growth inhibition) where response is reduced by half

Synthesis of aspirin