Anticancer Agents - Drug Design and Discovery - page 384

TMP TS

(5-FU, Alimta)

dUMP

1-Carbon chemistry ( N 5 , N 10 -CH 2 = THF)

F DHF THF

DHFR DHFR

(Methotrexate,
Alimta)

GARTF
(Alimta)

Purines
Methionine

Precursors

FIGURE 23.4 GARTF is one of the many enzymes involved in the biosynthesis of purines.

After exploring many options such as opening of the ring B, the best candidate was found to be
Alimta, developed and marketed by Eli Lilly (Figure 23.3E), which contains a fused pyrrole ring
in place of ring B. While early studies with Alimta showed that its primary target was TS, more
recent studies have demonstrated that following intracellular polyglutamation of Alimta the product
affects folate metabolism dramatically by inhibiting several folate-dependent enzymes: TS, DHFR,
GRAFT (Figure 23.4) in addition to aminoimidazole ribonucleotide formyltransferase (AICARFT),
and C-1 tetrahydrofolate synthetase (C1-S). This broad mechanism of action on folate activation may
be responsible for the efi cacy of Alimta. Today Alimta is used in pleural mesothelioma and as a
single agent for the treatment of patients with locally advanced or metastatic nonsmall lung cancer.

23.2.3 T AXOL
Another example of a successful anticancer drug whose development goes far back in time is taxol.
Back around 1960, the National Cancer Institute (NCI) launched a program of screening com-
pounds from plant extracts with the aim of identifying molecules of biomedical interest. Taxol was
discovered in 1963. This complex polyoxygenated diterpenoid was isolated from the pacii c yew,
Ta xus brevifolia , and later found in several other species of Taxus including Taxus wallichiana , the
Himalayan yew. By the early 1970s, the structure of taxol was solved (Figure 23.5A). Yet, another
decade had to pass before the molecular mechanism of the compound was elucidated, which is
stabilization of microtubules with concomitant cell cycle arrest at the G2M cell cycle phase. The
binding of taxol to polymerized -tubulin is depicted in Figure 23.5B. Later on availability prob-

lems associated with the limited supply of the Pacii c yew was solved by applying a semisyn-
thetic route starting with another natural product isolated from the English yew, Ta xus baccata ,
(10-deacetylbaccatin-III) avoiding the exhaustive complete synthesis of taxol. This was achieved
in the early 1980s, and accomplished by acetylating 10-deacetylbaccatin-III and attaching a side
chain to it. Taxol was i nally approved by the FDA at the end of 1992. Today, taxol (Paclitaxel)
developed and marketed by Bristol-Meyer Squibb is an effective drug in the treatment of breast-,
ovarian-, and lung cancer.
A total of more than 300 taxanes have now been made and extensive structure-activity rela-
tionship (SAR) analyses have been carried out. The most important i ndings are summarized here
(Figure 23.5A). In the lower part of the molecule, the activity is reduced by the removal of C1
hydroxy, C4 acetyl, 4,5,20 oxetane ring, and in the C2 benzoyl only limited substitutions are allowed.
In the upper part of the molecule derivatization of C7-hydroxyl or change in its stereochemistry has
no signii cant effect on activity. Also, reduction of a C9-ketone slightly increases the activity, and
both C10 hydroxyls and acetates retain activity. The C-13 side chain is essentially required for

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