THE LEADS FOR NEW PHARMACEUTICALS ARE DIFFICULT TO COLLECT BUT WE HAVE TRIED BEST TO EXPLAIN AND COVER THE MOST.

2. INTRODUCTION
 Cancer is a group of diseases involving abnormal cell growth with the potential
to invade or spread to other parts of the body
 Currently, the use of a large number of chemosynthesis of anti-cancer agents has
brought great harm to the human body, and the main drawback is to suppress the
immune system
 Tumour cells are highly sensitive and easily induce drug resistance
 Therefore, new anti-cancer drugs and therapies needs to be develop urgently
 Need for new therapeutic strategy, for example,
1. To improve the efficacy of natural compounds
2. To combine with chemical drugs and reduce toxicity as well as side effects;
increase selectivity and reduce the risk of using chemical medicine alone.
3. This can not only improve treatment efficiency but also overcome the
limitations of cell toxicity and adverse reactions

3. ANTICANCER DRUGS ARE :
a) Taxanes: Paclitaxel and Docetaxel
b) Podophyllotoxins: Etoposide and Teniposide
MECHANISM OFACTION :
 Taxane acts as an inhibitor of tubulin synthesis in G2 phase
 Podophyllotoxin acts as an inhibitor of assembly of microtubules and arrests the
cell cycle in metaphase
 Etoposide and teniposide inhibits DNA synthesis by forming a complex with
topoisomerase II and DNA. This complex induces breaks in double stranded
DNA and prevents repair by topoisomerase II binding
 Accumulated breaks in DNA prevent entry into the mitotic phase of cell division,
and lead to cell death. Both acts primarily in the G2 and S phases of the cell
cycle

4. PACLITAXEL AND DOCETAXEL
The English yew, Taxus baccata, contains highly toxic metabolites and their
potency and fast duration of action has often made extracts of yew the poison of
choice.
It is thus ironic that extracts from the Pacific yew, T. brevifolia, after being
tested in the National Cancer Institute's (NCI) screening program during the
1960s, yielded what was described as the most exciting anticancer compound
discovered in the previous 20 years; that is, paclitaxel (originally given the
name tax01 by Wall and Wani)
A. TAXANES

5. Paclitaxel
Basic Structure :-

6. SAR of Paclitaxel :-

7. LIMITATIONS:
The limited supplies of paclitaxel, the compound was very poorly soluble in water,
which made formulation difficult. However, various new assays were developed in
the 1970s, including the initial isolation and characterization of paclitaxel proved
particularly difficult because of:
(1) Its very low natural abundance in T. breuifolia bark (although this was the best
known source, the isolated yield was only 0.02% w/w, equivalent to 650 mg per tree)
(2) The poor analytical data obtained from the purified compound
(3) The failure of paclitaxel to give crystals that were suitable for X-ray analysis.
The structure of paclitaxel was published in 1971, but further biological testing
continued to be troubled by difficulties
(4)The compound showed only modest in vivo activity in various leukaemia assays,
which was no better than that displayed by a number of other new compounds at the
time

8. BIOSYNTHETIC PRECURSOR OF PACLITAXAL :
Several biosynthetic precursors of paclitaxel and two of these, baccatin III and
10-desacetylbaccatin III have been used to prepare paclitaxel semi-synthetically
R=COCH3 - baccatin III
R=H - 10-desacetylbaccatin III
These semisynthetic approaches also provide access to analogs with potential
advantages over paclitaxel itself. Structure-activity studies have shown that,
although the oxetane ring appears to be essential for activity

9.  Wide variation in the nature and stereochemistry of the C-13 ester side-chain
N-t-(butoxycarbonyl)derivative, docetaxel, which appears to be more potent
than paclitaxel and has better solubility characteristics, has been developed and
launched by Aventis for the treatment of ovarian, breast, and lung cancers
Fig. DOCETAXEL

10.  Various "protaxols" designed to release paclitaxel in situ under physiological
conditions, have been prepared by acylating the C-2' hydroxyl group. Nicolaou
et al. reported the synthesis of the sulfone, which is soluble and stable in
aqueous media, but is able to release paclitaxel rapidly in human blood plasma

11. Cabazitaxel was superior to paclitaxel and docetaxel because of its poor
affinity of p-glycoprotein due to the presence of methoxy group at C7 &
C10
This improve the property makes this drug effective against docetaxel
resistant tumors
This extra methoxy group also provide cabazitaxel with a unique ability to
the cross blood brain barrier
But clinical advantage of this property have not been explored yet
Cabazitaxel :

12. Paclitaxel

13. B. Podophyllotoxin
 Podophyllotoxin inhibits the polymerization of tubulin and develop diverse
derivatives of podophyllotoxin, such as, etoposide, etopophos and teniposide,
which have been developed and are currently use in clinics for treatment of a variety
of malignancies and in combination with other drugs
 Deoxypodophyllotoxin and lignanspodophyllotoxin from Podophyllum hexandrum
are secondary metabolites with potential cancer therapy. But the supply of natural
source is becoming increasingly problematic, which calls for the need for urgent
alternative sources
 Various plant selection methods and criteria were designed and applied in order to
select alternative sources of podophyllotoxin lignan analogues
 Renouard et al. (2011) developed and validated an efficient extraction protocol for
podophyllotoxin and deoxypodophyllotoxin from Juniperus species and applied it to
13 Juniperus species as an alternative source of the metabolites. Zhao et al. (2013)
found out that the HY-1 of podophyllotoxin derivatives function as multi-targeted
DNA topoisomerase II inhibitor; as anti-cancer cells proliferation and; induced
G2/M phase arrest in human colon cancer cells

14. Fig. Podophyllotoxin Plants

15. Fig. Deoxypodophyllotoxin Fig. lignanspodophyllotoxin

17. Etoposide and Teniposide
 These are the semisynthetic derivative of podophyllotoxin that exhibits antitumor activity
 Etoposide and its thiophene analog teniposide are used clinically to treat small cell lung cancer,
testicular cancer,leukemias,lymphomas and other cancers
Teniposide is more potent, more highly protein bound than etoposide ,and its uptake and binding to
cells is also greater
Etoposide Teniposide

18. •due to its lack of water solubility
•Etoposide phosphate is a water-soluble prodrug of etoposide that is rapidly and
completely converted to the parent compound after intravenous dosing
Etoposide PhosphateEtoposide

19. Basic Structure of PODOPHYLLOTOXIN Structure of GL-331
GL-331 is a new analog which is more potent than 2 both in vitro and in
vivo and retained cytotoxicity against resistant cells
It is currently under phase 2 clinical evaluation

20. Thank you....