Contribution of Paul Ehrlich in early chemotherapy and the development of parameters on which future drugs are developed.

1. “Founder of Chemotherapy”
Paul Ehrlich
Presented by:
Dr. Pratibha Tiwari

2. Nobel Prize of Physiology and Medicine 1908
Founder of Modern Chemotherapy
Contribution in the field of: Histology,
Haematology, Immunology, Oncology,
Microbiology and Pharmacology

3. • Standardization of manufacturing of Anti-Diphtheria serum
• Discovery of Salvarsan (arsphenamine): First Magic Bullet
• Synthesis of anti-bacterials
• Concept of chemoreceptor and chemotherapy
• Concept of concept of linking chemical structure of
compounds to their pharmacological activities
• Concept of developing resistance

4. Staining Procedures...
He concluded that strong affinities must exist between
biological structures and the stain applied.
 Studied entire spectrum of staining techniques and chemistry involved
 Differential staining of tissues using Methylene Blue
 First detect bilirubin in urine of the patients of Jaundice ( Diazo reaction)
 Stained and named “Mast cells” using alkaline dyes
 Differentiated Leukocytes into Basophils, Eosinophils and Neutrophils
 First showed nucleated RBCs and subdivided into Megaloblast,
Microblast, Normoblast and Poikiloblast
 Methylene blue also stained the long appendages of nerve cells
 Developed a new staining procedure for Mycobacterium which later
became basis of current Zielh-Neelsen Acid- fact staining

5. Serum research...
• Formulated “Side-chain Theory” proposing a possible explanation for the
process of immunity.
• Gave concept of acquired immunity and mechanism of transfer of immunity
from mother to foetus.
• Alongwith Emil Behring work on Standardization of Anti-Diptheria serum
production process : “Valency of serums”
Side-chain Theory
• Introduced the term “Receptor”, developed the theory of chemoreceptor.
• A side-chain from a given cell might have a molecular structure that allowed it
to bind with a specific toxin or bacteria leading to its loss of action.
• This leads to trigger production of more such side-chains and secreted in the
blood. This way small amount of toxin of toxin can produce a large amount of
anti-toxin.
• Ehrlich later argued that certain chemoreceptors on parasites,
microorganisms, and cancer cells would be different from analogous
structures in host tissues, and that these differences could be exploited
therapeutically

6. Chemotherapy:
• In vivo staining
• Methylene blue as anti-malarial agent
• Transition from Experimental pharmacology to Therapeutic
pharmacology
• The search for a “Chemotherapia specifica” : concept of Structure–
Activity Relationship
• Development of first synthetic chemotherapeutic agent: From Atoxyl to
Salvarsan and Neosalvarsan against syphilis
Cancer research:
• Achieved insight that when tumors are cultivated by transplanting tumor
cells, their malignancy increases from generation.
• If primary tumor is removed, then metastasis precipitously increases.

7. Paul Ehrlich’s Magic Bullets:
If a compound could be made that selectively targeted a
disease-causing organism, then a toxin for that organism
could be delivered along with the agent of selectivity.
• Need to study the relationship between the chemical
composition of drugs and their mode of action in the
organisms
• Selective drugs were needed which, like anti-toxins
aimed specifically at their corresponding toxins
• High parasitotropism with low organotropism

9. DEVELOPMENT OF ARSENICALS

10.  In 1858, David Livingston suggested use of 1% aqueous solution of
potassium arsenite(Fowler’s reagent) for the treatment of sleeping
sickness
 1859- first synthesised ‘Atoxyl’ (Aminophenyl arsenic acid) by Pierre Jaceus
Antoine Be’champ
 Paul Ehrlich and Alfred Bertheim first derived structure of Atoxyl
 Atoxyl : high doses for prolonged period were required(2% patients get
optic nerve atrophy) in use till 1905.
 Acetylatoxyl (arsacetin): less toxic but high doses needed ; damage to
vestibular nerve
 Arsenoxides and Arsenobenzenes (reduced products; metabolites)
 Arsenophenyl glycine: effective against sleeping sickness, low toxicity,also
effective against spirochetes or syphillis; 1907
 Arsenophenol

11.  Arsphenamine or Salvarsan (Ehrlich and Hata; 1909 against syphillis):30%
arsenic, treatment 18 months long with 20 arsphenamine injestions and
30-40 bismuth injections; difficult to prepare on large scale
 Neoarsphenamine or neosalvarsan: sodium bisulphite aldehyde
derivative; 19 % arsenic, less toxic , short treatment time, easily oxidised
 In 1930 Mapharsen (oxophenarsine, metabolite of arsphenamine) very
stable.
 Melarsobol or Arsobal, injectable arsenic derivative remains in use as the
treatment of choice for sleeping sickness.

12. Atoxyl
(arsernic acid anilide)
Atoxyl
(Aminophenyl arsenic acid)
Acetylatoxyl
Arsacetin
Spirasyl
(arsenophenylglycine)
Arsenophenol
Arsphenamine
(diaminodioxyarsenobenzol)
Salvarsan
Neoarsphenamine
Neosalvarsan
Oxophenarsine
Mapharsen
Melarsoprol
Arsobal
Trimers and Pentamers
Of arsphenamine
(Salvarsan main constituents)

13. Development of Sufanilamides

14. Sulfa drugs or Sulfanilamides
• First synthetic chemotherapeutic agent effective against bacterial disease.
• Gerhard Domagk(1932) hypothesized that since the dye worked by
binding to the proteins in fabric and leather, it might also bind to the
proteins in bacteria , thus inhibiting their action
• In 1936, Prontosil or sulfamidochrysoidine, a dye, was successfully used
against puerperal sepsis, also effective against meningitis , pneumonia,
and streptococcal infections, childbed fever, blood poisoning, gonorrhea,
burns from gas warfare, and other serious burns
• Most effective sulfa drugs were sulfapyridine for pneumonia,
sulfathiazole against pneumonia and staphylococcus, sulfaguanadine to
treat dysentery , and sulfadiazine, which worked against pneumonia,
strep and staph.
Prontosil

15. Prontosil

17. SAR of sulphanilamides