anticancer drugs which is usen majorly and their limitation.

1. ANTICANCER DRUGS
Presented by
Mr. SURAJ N. WANJARI
M.Pharm. 1st Sem.Pharmaceutical Chemistry
University Department of Pharmaceutical Sciences,
Rashtrasant Tukadoji Maharaj University Nagpur, Nagpur -440 033.

2. INTRODUCTION
 Today, cancer is a serious hazard to human health and affects the lives of
millions of people. Cancer has become the second largest cause of death after
cardiovascular diseases
 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
 Even though conventional anti-carcinogen play an important role in the
treatment of most solid tumours, there are limitations in the use of single
chemotherapeutic drug as anti-tumour treatment agent; such as, emergence of
drug resistance, high cell toxicity and limited regime of clinical uses

3.  Therefore, there is 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
ANTICANCER DRUGS ARE :
a) Taxanes: Paclitaxel and Docetaxel
b) Podophyllotoxins: Etoposide and Teniposide

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)
Paclitaxel

5. 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

6.  Phase I clinical trials were initiated in 1983, but these were to proceed at a slow
and tortuous pace and proved all but disastrous when the high levels of oil-based
adjuvant used to formulate paclitaxel caused severe allergic reactions in many
volunteers. Undaunted by the formulation problem and spurred on by paclitaxel's
novel mechanism of action, clinicians were able eventually to minimize the
allergic events and demonstrate useful activity
 Phase II clinical trials began in 1985 despite continuing supply problems, and 4
years later the program received a significant boost when McGuire et al. reported
good responses from patients suffering from refractory ovarian cancer, a disease
that kills some 12,500 women a year in the United States alone

7. Mechanism of action of taxol:
Fig. Cell cycle

8. Structure-activity relationship of paclitaxel:

9. 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 semisynthetically.
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.

10.  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

11.  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.

12. 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.

13. Fig. Deoxypodophyllotoxin Fig. lignanspodophyllotoxin

14. Etoposide and Teniposide
These are the semisynthetic derivative of podophyllotoxin that exhibits antitumor activity.
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.
Fig. Structure of etoposide Fig. Structure of Teniposide

15. Thank you