1. Pharmaceutical Chemistry II Steroids Joseph O. Oweta | PHC 3201

2. Androgens Are male hormones, also known as androgenic Hormones or testoids. Besides specific actions on gonads, they stimulate production of elements that are absolutely essential for tissue growth. Anabolic steroids are synthetic variants of testosterone that are abused in an attempt: – to promote muscle growth, – enhance athletic or other physical performance, – and improve physical appearance.

3. Structure Activity Relationships General Considerations For a substance to have androgenic activity, it must contain a steroid skeleton. Oxygen functional groups at C 3 & C1 7 are not essential because the basic nucleus, 5α androstane has androgenic activity. Ring expansion to form a homo derivative by inserting a methylene group into one of the rings of the nucleus or ring contraction (removing a methylene group) significantly reduces or destroys the androgenic and anabolic activities.

4. Structure Activity Relationships Oxygen Functional Groups Introduction of a 3 – ketone or 3α – OH enhances androgenic activity. No known substituent can approach the 17β-OH group. Long acting esters of the 17β-OH compounds are hydrolysed in vivo to the free alcohol. The 17β-Oxygen atom may be important for attachment to the receptor site.

5. Structure Activity Relationships 17α-substituents 17α-substituents render the compounds orally active. They are important for preventing metabolic changes at the 17 Position. Increasing the length of the alkyl chain results in decreased activity. Inc. of other substituents produced progestins (progestational activity) e.g. ethisterone (ethynyl group)ethisterone

6. Ethisterone

7. Structure Activity Relationships Other considerations Modifications of 17α-methyltestosterone lead to potent, orally active anabolic agents. Hydroxylated analogues e.g. oxymetholone have at least three times the anabolic and half the androgenic activity. Halognenated produces compounds with reduced activity except when inserted at positions 4 or 9 (e.g fluomesterone) Subsitution of C 2 with oxygen (oxasteroid) has produced the only clinically successful steroid. (

8. Testosterone 17β-hydroxyandrost-4-en-3-one Rapid Metabolism to 17 ones

9. Synthesis of Testosterone* *Butenandt (1935) ; Ruzica (1935) ; Oppenauer (1937)

11. Synthesis of Testosterone – 2/2

12. Methyltestosterone 17β-hydroxy-17-methylandrost-4-en-3-one Orally Active ½ Testosterone Activity

13. Androsterone 3α-Hydroxy-5α-androstan-17-one.

14. Synthesis?!

15. Fluoxymesterone 9α-fluoro-11β-dihydroxy-17-methylandrost-4-en-3-one X10 testosterone potency Same indications

16. Oxymetholone Approved for anaemias

17. Oxandrolone Promotion of weight loss Surgery Chronic infections HIV wasting Others

18. Antiandrogens Read and make notes on: – SAR’s – Structures

19. Break!

20. Oestrogens Active endogenous oestrogen are: – Estradiol – Estrone – Estriol Activity parallels in vivo ER affinity. Activity is also affected by interconversions. Comparative Activity

21. Oestrogens Classification Steroidal Oestrogens Non-steroidal oestrogens/ DES derivatives Phytoestrogens – Congeners of the Steroidal/ DES derivatives – Of Plant Origin!

22. Oestrogens Therapeutic Uses Birth Control – Inhibition of ovulation in combination with progestins. Hormone replacement therapy – Post menopausal women. Oestrogen Deficiency – Ovarian Failure – Oophorectomy Rx of advanced inoperable Breast Cancer: – Men – Postmenopausal Women

23. Structure Activity Relationships Read and make notes on the oestrogen SAR’s with reference to the Article by V. Craig Jordan et al.(See the Learning Management System*) Can you relate the SAR’s to the activity of the selected Compounds in subsequent slides? *http://lms.must.ac.ug/

24. Estradiol Estra-1,3,5(10)-triene3-17β-diol

25. Estrone 3-Hydroxyestra-1, 3, 5 (10)-trien-17-one

26. Estriol Estra-1,3,5 (10-triene-3,16α,17β- triol

27. Diethylstilbesterol Derivatives

28. Structure Activity Relationships DES may be viewed as a form of estradiol with rings B and C open and with a 6-C ring D

29. DES SARs The distance between the two DES phenol OH groups is 12.1Å while that between 3-OH 17-OH is 10.9 Å in Estradiol. In aqueous soln., estradiol has 2 H 2 O molecules at 17-OH and if factored in the distance measurement, there’s a prefect fit..

30. Superimposition of DES and Estradiol

31. DES SARs Therefore, oestrogens need a phenolic moiety for activity. The distance between OH groups in the DES analogues is required for activity of the analogue. Conformity ( 2 ethyl/ other alkyl derivatives) and rigidity(Central Double Bond) are important for oestrogen activity

32. Importance of Conformity and Rigidity Hexestrol is a reduction product of DES with diastereoisomers 12.1 Å Steric repulsion

33. DES Can you assign a systematic name to the structure Draw the structure of – Dinestrol

34. Notable A/E’s Oestrogens and Cancer – Increased Risk of Breast Cancer with use DES babies – Female babies exposed in utero High risk of infertility

35. The end