STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 103

infers comparable activities. The design and syntheses of several D-seco, oxirane,
and cyclopropane analogs were realized and biologically tested by a Dutch
group. 143 The lower activities of those analogs than paclitaxel by three orders of
magnitude may also be partly attributed to the absence of the 4-acetoxy group,
which was demonstrated earlier 141 in addition to the absence or inappropriate
arrangement of the oxygen atom of the oxetane D ring in space.

3.2.6 Macrocyclic Analogs

Ojima et al. proposed a common pharmacophore for several anticancer natural pro-
ducts targeting microtubules, including paclitaxel, epothilones, eleutherobin, and
discodermolide. 144 It was suggested that macrocyclic taxoids such as 99a may
represent hybrid constructs of paclitaxel and epothilone. A group of these macro-
cyclic taxoids with unsaturated and saturated linkages between C-2 and C-3 0 were
prepared through ring-closure metathesis (RCM) catalysed by the Grubbs catalyst
and subsequent hydrogenation. 145 Among 30 macrocyclic taxoids, only three of
them, including 99a, retained strong cytotoxicity, although they were less active
than paclitaxel by two orders of magnitude. Taxoid 99a was also one of three active
taxoids in tubulin polymerization assay with 36% relative activity to paclitaxel.
Boge et al. also prepared a group of macrocyclic taxoids, in which C-2 benzoate
and C-3 0 phenyl were tethered by alkenyl, alkyl, and ester linkers. The alkenyl
linked taxoids were synthesized through Heck reaction, and additional hydrogena-
tion formed alkyl linkage. All compounds subjected to tubulin polymerization tests
were inactive. Unfortunately, the authors did not report the biological evaluation
and molecular modeling results of the precursors for those C2-C3 0 tethered ana-
logs, which may provide insight to their questions on the ''hydrophobic collapse''
hypothesis. 146
Ojima et al. also completed the synthesis of a series of C3 0 N-C2 linked macro-
cyclic analogs of 3 0 -isobutyl analogs by RCM strategy. 147 Interestingly, most ana-
logs in this series were more potent cytotoxic agents against LCC6 human breast
carcinoma and its drug-resistant counterpart LCC6-MDR than were the C3 0 -C2
linked macrocyclic taxoids through a meta-substitutent on C-2 benzoate, although
they were still less active than paclitaxel by one to two orders of magnitude. Tax-
oids 99b and 99c were among the most potent inhibitors for both wild-type and
drug-resistant cancer cells. A CNRS group also demonstrated the impact of ring
size for C3 0 N-C2 tethered taxoids through C2 aliphatic ester groups by RCM
and sulfide at the end of C3 0 -N amides and C-2 aliphatic esters, 148 and they com-
pared the cytotoxicities of the macrocyclic taxoids with their open-chain counter-
parts. They concluded that the sulfide linkage is deleterious to the activity 148 and
that the 22-membered ring taxoid was active, whereas 18-, 20-, and 21-membered
ring taxoids were inactive in tubulin binding and cytotoxicity assays. 149 Also, tax-
oids with both C-3 0 N and C-2 alkyl acyl groups (open-chain taxoids), although they
exhibited several times weaker binding affinity and cytotoxicity than docetaxel,
they were still one to two orders of magnitude more active than their macrocyclic
derivatives.