Story of Cis-Platin

8/14/2019 Story of Cis-Platin

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History of thegreatinvention in

science



"God didn’t make"God didn’t make

anything soanything socomplicated that itcomplicated that it

’ "’ "



Barnett

Rosen



Mitosis cell division



Magnetic and Electric Field Lines



• To study the effect of electric fields onCell Division (like Mitosis)

• Started with Escherichia coli bacterialcells

Idea !



• An audio oscillator was used to supplysinusoidal voltages of 50 to 100,000

cycles/second (c/s). These signals wereamplified by a conventional audio power amplifier and then sent to a pair of

platinum electrodes in the chamber

Experimental Setup





Result ?



• Bacterial cells stopped dividing andstarted to elongate and forming long

filaments• After the voltage was removed, the cells

continued to increase in length, but after

2 hours had elapsed, cell division startedto occur again.

When Freq. was 500 - 6,000 c/s



• At 500 c/s, filamentous growth was at amaximum

• At 6,000 c/s, no filaments could be seen• For 6,000 to 100,000 c/s no filament

could be seen even after 24 hr

Effect of Frequency applied



• Filamentous growth occurred at thefrequencies mentioned above only when

oxygen was present• If nitrogen or helium, were bubbled

through the cell, no effect was observed

Role of atmosphere



•

The filamentous growth can be caused by٭ Dyes such as methylene blue and penicillin

٭ Transfer to an unaccustomed medium

٭ Osmotic pressure changes٭ Near ultraviolet irradiation

٭ Magnesium deficiency or excess

٭ Temperature٭ pH

Control Experiments



The application of an electric field to the bacterial medium might have led to an

electrolysis reaction and that thechemical products of this reaction mighthave affected bacterial cell division



ELECTRODE

and CULTURE

BACTERIA and

CULTURE



• The application of the electric currentwas not itself responsible for theobserved effects on bacterial growth

• Rather that the electric current led to theformation of a new chemical species thataffected bacterial elongation

• Oxygen had to be present for bacterialelongation to occur



• It gives positive result to the potassiumiodide-starch testM2+ + 2 I- M0 + I2 redox reaction

I- + I2 I3- acid-base reaction

M2+ + 3 I- M0 + I3

- net reaction

• Ordinary medium gave no reaction with potassium iodide and starch

Is an Oxidizing agent?



Intensity of the blue colorcorresponded to the frequency of theapplied voltage

The frequency was 500 c/s, the bluecolor was most intense

The frequency was 6,000 c/s, the blue

color was not detectable



•

Several possible oxidizing agents could becreated from the medium during electrolysishypochlorite ion (ClO-)

chlorite ion (ClO2-)

chlorate ion (ClO3-)

perchlorate ion (ClO4-)

hydrogen peroxide (H2O2)

hydroxylamine (NH2OH) persulfate ion (S2O8

2-)

Who is the mystery oxidizing agent?



•Phosphate ion (PO4

3-

)• Sulfate ion (SO4

2-)

• Phosphate ion + glucose

• Phosphate ion + sulfate ion + glucose

• Sodium sulfate ( Na2SO4)

•

Sodium carbonate ( Na2CO3)

Negative results-(Starch iodide Test)



• Ammonium sulfate ((NH4)2SO4)

• Ammonium carbonate ((NH4)2CO3)

• Ammonium chloride ( NH4Cl)

• Sodium chloride ( NaCl) gave a faint positive response

Positive results-(Starch iodide Test)



Platinum electrodes could be attacked

by an acidified chloride solutionduring electrolysis, generating PtCl62-

Clue!



• (NH4)2PtCl6 was shown positive potassium iodide-starch test(>100 ppm)

• A later account suggests that (NH4)2PtCl

6

at first caused cell death then later, after standing on a laboratory shelf for a fewweeks, produced a small number ofilaments

Later Results…



Cobalt (Co)Iridium (Ir)

Nickel (Ni)

Osmium (Os)Palladium (Pd)

Rhodium (Rh)

Ruthenium (Ru)Platinum-containing compounds





(NH4)2PtIVCl6+ uv light PtIV(NH3)2Cl4





Cisplatin coordinates to DNA and thatthis coordination complex not only

inhibits replication and transcription of DNA, but also leads to programmed celldeath (called apoptosis)

Action of Cisplatin



Cisplatin in cell level



Binding site in Base Pairs…





Geometrical Isomer



•

In vitro studies on both prokaryotic andeukaryotic cells revealed that DNA adducts of both cisplatin and trans-DDP blocked theaction of DNA polymerase

• In vivo studies showed that cisplatin andtrans-DDP inhibited replication equally well

• DNA replication is not the only factor

important for the clinical activity of cisplatin



The cytotoxic activity of cisplatin may

arise from the cell’s inability to repair DNA damage caused by cisplatin.



•

The cell detects DNA damage by the actionof damage recognition proteins

• HMG-domain proteins bind cisplatin–DNA

adducts in vitro• In vivo assays on yeast shown that HMG-

domain proteins are important for theactivity of cisplatin:

• These effects may also be in operation inmammalian cells



1. HMG domain containing transcriptionfactors bind preferentially to thecisplatin–DNA adducts, they could

wreak havoc with the transcriptionalmachinery

2. When HMG domain proteins bind to

the cisplatin–DNA adducts, the adductswould not be recognized by the repair machinery

Role of HMG domain proteins



DNA-Cisplatin-HMG adduct







• Acquired resistance

–Drug is initially beneficial but becomes

ineffective over time• Intrinsic resistance

–Drug is ineffective from the outset

Drug Resistance



• Decreased Intracellular Accumulation

• Sulfur-Containing Macromolecules

• Increased DNA Repair

Resistance Mechanism



• Thrombocytopenia

• Leukopenia

• Anemia• Nephrotoxicity

• Ototoxicity

Side Effects



Cisplatin was approved as an anticancer drug in 1978 by the Food and Drug

Administration



$250 million in royalty !!!



Synthetic path way of Cisplatin



"In the fields of observation,"In the fields of observation,

chance favors only the mindchance favors only the mindthat is prepared " - Louisthat is prepared " - LouisPasteurPasteur



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Story of Cis-Platin