Chemistry of Natural Products

1. Presented by:-
Siddharth Shekhar Singh

2. Steroid hormones and related products represents
one of the most widely used classes of therapeutic
agents.
Steroid hormones in mammals are biosynthesized
from Cholesterol, which in turn is made in vivo from
acetyl-coenzyme A(acetyl-CoA) via the mevalonate
pathway.
Cholesterol synthesis occurs in smooth ER and
enzymatic conversion occur in mitochondria.

3. Steroid hormones are classified in to two types:-
1.Adrenal cortical hormones
2.Sex hormone
The adrenal cortex secrets steroidal hormone which have
1.Mineralocorticoids-Aldosterone
2.Glucocorticoids- Hydrocortisone
3. Sex Hormones-Androgen and Estrogen.

4. Adrenal cortex-mineralocorticoids, glucocorticoids,
adrenal androgens.
Adrenal medulla-catecholamines eg: epinephrine.

5. Outer zone (zona glomerulosa)-secretes
mineralocorticoids.
Inner zone(Zona fasciculata and reticularis)-secrete
glucocorticoids and adrenal androgens.

7. Adrenocorticoids are a class of chemicals that includes the
steroid hormones that are produced in the adrenal cortex
of vertebrates and synthetic analogues of these hormones.
Corticosteroids are involved in a wide range of
physiological processes, including stress response, immune
response, and regulation of inflammation , carbohydrate
metabolism, protein metabolism, blood electrolyte levels
and behaviour.

8. Glucocorticoids: Such as cortisol control carbohydrate, fat and
protein metabolism , and anti-inflammatory by preventing
phospholipid release, decreasing eosinophil action and a
number of other mechanism.
1.Hydrocortisone.
2.Cortisone acetate.
Mineralocorticoids: Such as aldosterone control electrolyte
and water levels, mainly by promoting sodium retention in the
activity. Eg: Aldosterone,Deoxycortisone.

13.  All cortical steroids contains alpha, beta- unsaturated
ketones in ring A and COCH2OH moiety attached to
C-17 that has beta configuration. These requirement
are essential for mineralo corticoid activity.
 Oxygen at C-11is essential for glucocorticoid activity.
A hydroxyl group is superior to C-11keto group.
 A 17 alpha group increases glucocorticoid activity.
 Introduction of a fluoro to 6 alpha position increases
both mineralocorticoid and glucocorticoid activity.

14. Insertion of double bond at C-1,2 position enhance the
glucocorticoid and anti-inflammatory activity.
Introduction of methyl or hydroxyl at C-16 diminishes the
mineralocorticoid

16.  All steroid hormone have in common the 17- carbon
cyclopentanoperhydrophenanthrene nucleus.Additional carbons
can be added at positions 10 and 13 or as a side chain attached to
C17.
 Uptake of cholesterol by the adrenal cortex is mediated by the LDL
receptor.With long-term stimulation of the adrenal cortex by
ACTH,the number of LDL receptor increases.Much of the
cholesterol in the adrenal is esterified and stored in cytoplasmic
lipid droplets.
 Upon stimulation of the adrenal by ACTH or Camp, an esterase is
activated, and the free cholesterol formed is transported into the
mitochondria.

18.  In the mitochondria, a cytochrome P450 side chain cleavage
enzyme converts cholesterol to pregnenolone.

19.  Pregenolone may be converted by dehydrogenase/isomerase to
progesterone or else by P450c 17( 17 alpha hydroxylase) to 17
alpha hydroxy pregnenolone. Progesterone can also be converted to
17 alpha hydroxy progesterone.

20.  After the synthesis of progesterone and 17-
hydroxyprogesterone,P450c21 (21-hydroxylase) can hydroxylate
these steroids at the 21 position, resulting in 11-
deoxycorticosterone and 11- deoxy cortisol, respectively.

21.  The final step in the synthesis of adrenal mineralocorticoids
and glucocorticoids is mediated by P450c11(11-beta
hydroxylase), which also mediates the final step in the
synthesis of aldosterone from deoxycorticosterone.

22.  Addison Disease: medication given is hydrocortisone to treat
it.20- 40mg.
 Cushing Syndrome: Cushing syndrome is caused by a hyper
secretion of glucocorticoids that results from excessive
release of corticotrophin.
 Hydrocortisone 300mg IV on the day of surgery.
 Non endrocrine disease
1.Rheumatic disorder- suppress the disease and minimize
resultant tissue damage. Prednisone 10mg/kg/day.
2.Allergic disease-epinephrine 0.5ml of a 1:1000solution IM.

23.  The effect of Corticosterone,
cortisone,Desoxycortisone and Hydrocortisone
on Rat Uterine contractility at Oestrus.(1966)
There is marked increase in blood and urinary levels of
adrenocorticoids and their metabolites during pregnancy in
women(Loraine and bell 1966).The general purpose of this
elevation is presumably related to the need for conservation of
energy required during development of the uterus, placenta and
foetus. However , the considerable elevation of steroid hormones
can be expected to effect uterine contractility.

24.  Adrenocorticoids control 5 –hydroxy tryptamine metabolism
in rat brain.
The influence of surgical adrenalectomy was examined on the biosynthetic
capacity for 5-hydroxytryptamine of rat brain.The results demonstrate that
adrenalectomy decreased tryptophan hydroxylase activity and its substrate
tryptophan in the brain stem.
The adrenocortical hormone regulate brain 5-hydroxytryptamine synthesis
probably by enhancing both the levels of tryptophan and the activity of rate
limiting enzyme tryptophan hydroxylase. It is postulated that emotional
instability seen during altered adrenocortical function might partly be
associated with abnormal metabolism of central 5-
hydroxytryptamine.(published in 2003by R.B.Rastogi and R.L.Singhal)

25.  Relative adrenocorticoid insufficiency exists and should be
treated.
 The issue of relative adrenocortical insufficiency(RAI) in septic shock
is uncertain. It is defined as an increment of less than 250nmol/L in
total serum cortisol level after administration of 250 microgm
corticotropin.RAI is associated with increased risk of death, after
adjustment for other factors that might independently influence risk.
There is strong , but not overwhelming, evidence that administration
of low doses of hydrocortisone to patient with septic shock,
especially those with RIA improves survival.(Article2006 )

26.  Prednisone and prednisolone are steroids widely used as anti-inflammatory drugs.
Development of the pharmaceutical industry is currently aimed at introducing
biotechnological processes and replacing multiple-stage chemical syntheses. In this work we
evaluated the ability of bacteria belonging to the Rhodococcus genus to bio transform
substrates, such as cortisone and hydrocortisone, to obtain prednisone and prednisolone,
respectively. These products are of great interest from a pharmaceutical point of view as they
have higher anti-inflammatory activity than the starting substrates. After an initial lab-scale
screening of 13 Rhodococcus strains, to select the highest producers of prednisone and
prednisolone, we reported the 200 ml-batch scale-up to test the process efficiency and
productivity of the most promising Rhodococcus strains. R. rubber, R. globerulus and R.
coprophilus gave the Δ1-dehydrogenation products of cortisone and hydrocortisone
(prednisone and prednisolone) in variable amounts. In these biotransformations, the
formation of products with the reduced carbonyl group in position C20 of the lateral chain of
the steroid nucleus was also observed (i.e., 20β-hydroxy-prednisone and 20β-hydroxy-
prednisolone). The yields, the absence of collateral products, and in some cases the absence
of starting products allow us to say that cortisone and hydrocortisone are partly degraded.

27.  Steroidal hormones were isolated from the adrenal cortex in the 1930s and were
synthesized a decade later. Several of these structures have highly effective anti-
inflammatory activity but also exhibit serious side effects. Chemical analogues have
now been discovered with better activity and reduced side effects. Such agents are
administered for the treatment of a wide range of inflammatory conditions,
including rheumatoid arthritis and asthma. Anti-inflammatory activity can be
improved by introducing functional groups or substituents at key positions of the
steroid structure. Similarly, substituents placed at key positions can reduce side
effects and metabolic susceptibility. Nevertheless, there are still risks associated
with the long-term use of steroids, and research is currently looking at novel agents
that will act locally at the site of administration and are rapidly metabolised to
inactive compounds once they reach the blood supply.

28.  Advances in steroid methodology make possible a direct
approach to the problem of the nature of the secretion of the
human adrenal cortex. Two experimental studies in which
adrenal venous blood was analyzed (1, 2) indicate that 17-
hydroxycorticosterone and corticosterone are components of
the steroid mixture elaborated by the human adrenal. These
two steroids have also been reported to be present in the
peripheral blood of man.

29.  Organic Chemistry of Natural Products Vol I and Vol II by
Gurdeep and Chatwal
 Organic Chemistry of Natural Products by O.P. Agarwal
 Steroids and Hormones by V.K.Ahluwalia.
 Steroids Hormone Receptor by C.R. Clark.
 https://journal.chestnet.com.
 https//pubmed.ncbi.nlm.nih.
 https//pubs.acs.org.

30. THANK YOU