Nosh Aspirin

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