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3 Structure–Activity Relationships (SAR) of Taxol

3 Structure–Activity Relationships (SAR) of Taxol

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134



4 Taxol, Taxoids, and Related Taxanes



d)

e)

f)

g)



The A-ring is necessary for cytotoxicity.

The C2 benzoyl group is essential for biological activities.

The 4-acetyl group is essential for biological activities.

The epimerization or acetylation at C7 does not affect the biological activity

significantly.

h) C10 esters other than acetate and C10-deacetyl (i.e., C10-OH) and C10deacetoxy analogs are active.

i) The oxetane ring is essential for biological activities.

These initial observations guided the site-specific modifications of taxol. The

results of subsequent extensive SAR studies have been summarized in excellent

reviews [117–121].

4.3.2

Chemical Modifications of Taxol: Taxol Derivatives and Taxoids

4.3.2.1 Modifications in the C13 Side Chain

C20 -Position: Protection of the C20 hydroxyl group with silyl groups such as TBDMS

or replacing it with fluorine led to substantial decrease in activity [114,119,122].

Potier and coworkers examined all the possible diastereoisomers to study the effect

of stereochemistry at the C20 - and C30 -positions and concluded that the natural

configuration (20 R,30 S) was the most potent for inhibition of microtubule

disassembly, whereas (20 S,30 R) was almost inactive [123]. Several “prodrugs” were

developed by acylating this position, which are discussed in Section 4.3.2.3.

C30 - and C30 N-Positions (Figure 4.3): During the investigation into the semisynthesis of taxol, a t-butoxycarbonyl group was used as the amine protecting group of

the phenylisoserine component. Naturally, all key intermediates and their simple

derivatives were evaluated for their tubulin polymerization and microtubule

stabilization as well as cytotoxicity. Then, docetaxel (18) emerged as the first

synthetic analog of taxol, exhibiting higher potency than that of taxol [116]. Also, the

term “taxoid” (i.e., taxol-like compound) was introduced to represent a new class of

synthetic taxanes. Docetaxel (18) was approved by the FDA in 1996 and has become

another major anticancer drug equivalent to taxol [14]. The clinical development of

docetaxel is discussed in detail in Section 4.6.1.

As a part of the SAR study of docetaxel, taxoid 19, bearing a cyclohexyl group in

place of a phenyl group at C30 , was prepared and its biological activities examined.

Taxoid 19 exhibited almost the same activity as that of docetaxel (i.e., better than

taxol) in the microtubule disassembly inhibition assay and comparable cytotoxicity to

docetaxel against P388/Dox cell line [124]. This result clearly indicated that the C30

phenyl group is not a requisite for the biological activities of taxol and docetaxel. In a

similar manner, the activity of butitaxel 20 in microtubule stabilization and

cytotoxicity assays against B16 melanoma cell line was found to be better than that of

taxol [125]. However, the introduction of smaller alkyl groups at the C30 -position

resulted in the significant loss of activity. For example, the C30 methyl analog of

docetaxel showed a 19-fold decrease in microtubule stabilization activity [123].



4.3 Structure---Activity Relationships (SAR) of Taxol



O



NH



OH



O



HO



O



O



O

O



OH



18

docetaxel



H

OH O OAc

O

Ph



O

OH



19

HO



NH



OH



20

MeO



O



O



21

cabazitaxel



H

OH O OAc

O

Ph



O



O

HO



O



O O



NH O



O

O



O



OH



H

OH O OAc

O

Ph



O OMe



NH O



OH



H

OH O OAc

O

Ph



O

O



O



O OH



NH O



O



O

N

H



HO



O



O



O



O



OH



H

OH O OAc

O

22

Ph

milataxel



O



Figure 4.3 Modifications of the C13 side chain.



A combination of modifications at the C30 -, C7-, and/or C10-positions led to the

development of another FDA-approved taxoid, cabazitaxel (21), and a clinical

candidate, milataxel (22). The clinical studies of these taxoids are discussed in

Sections 4.6.2 and Sections 4.6.6, respectively.

Conformationally restricted macrocyclic analogs 23 with alkyl, alkenyl, and ester

tethers between the C2 benzoate and C30 phenyl groups were much less active than

taxol [126]. In contrast, macrocyclic taxoids with a vinylidene linkage between the

C2 benzoate and C30 N-benzoyl linkage such as 24 exhibited a good activity

(IC50 ¼ 67 nM) against the LCC6-WT human breast cancer cell line [127].

Photoreactive taxol analog 25a was synthesized [128] by introducing a benzophenone moiety into the C30 N-position as a useful photoaffinity labeling agent to

identify the taxol binding sites on tubulin as well as Pgp (Figure 4.4) [129].

4.3.2.2 Modification in the Baccatin Component

Ring A (Figure 4.5): Deoxygenation at C1 was shown to cause a slight reduction in

activity [33]. Most synthetic A-nor analogs were less active than taxol, with the

exception of compound 26, which was comparable to taxol in the tubulin

polymerization assay and half as cytotoxic as taxol against the CA46 human

lymphoma cell line [130]. Nor-seco-taxoids (27), derived from 14b-hydroxy-10-DAB

(6), were 20–40 times less cytotoxic than taxol against several human cancer cell

lines, but comparable to taxol against drug-resistant MCF7-R (NCI/ADR) cell line

[131]. Taxoids derived from 14b-hydroxy-10-DAB are discussed in Section 4.4.2.



135



136



4 Taxol, Taxoids, and Related Taxanes



AcO



Ph



O



O



H

N



H

OH O OAc

O



O



O



O OH



AcO



OH



O



OH



O



HO



O



O



OH O OAc

O



O

Ph



N

H



tether

23



O



24



tether =



O

c



b



a



3H



O



AcO



O

NH



O



3H



Ph



H

OH O OAc

O

Ph



O



O



OH



OH

25a



O



Figure 4.4 Macrocyclic taxoids and photoaffinity labeling taxoid involving modifications in the C13

side chain.



O

AcO



O

Ph



NH



O



OH

R



O

O



O



O

HO



O

26



O



OH



OBz OAc



OH



O OH



O



Ph

O



Ph



NH



27



OBz OAc



a: R = Ph

b: R = Boc



Figure 4.5 Examples of A-ring modified taxoids.



Ring B, C2-Position (Figure 4.6): Deoxygenation, hydrolysis, and epimerization at

the C2-position of taxol resulted in significant loss of activity [132,133]. Taxol

derivatives 28a–28d were synthesized through selective hydrolysis of the benzoate

and reacylation with a meta-substituted benzoate at C2 [134]. These taxol derivatives

were substantially more potent than taxol against P-388 murine and HL-60 human

leukemia cell lines. In particular, 28a was at least 10-fold more cytotoxic than taxol

in five cancer cell lines of the NCI tumor panel screen and 100-fold more active

than taxol in the tubulin polymerization assay [134]. In contrast, the corresponding

taxol derivatives bearing the same substituents at p-position of the C2 benzoate

group were an order of magnitude less active than taxol against the same cell lines.

These results seemed to indicate, at that time, that the meta-substitution of the C2

benzoate enhanced the “hydrophobic collapse” [135] interaction with the C30



4.3 Structure---Activity Relationships (SAR) of Taxol



O

AcO



O

Ph



NH



O



OH



O



Ph



O

O



OH



H

OH O OAc

O



28

a: X = Cl; b: X = OMe

c: X = N3; d: X = CN X



O



O



O



O

NH



OH



O



Ph



O

OH



H

OH O OAc

O



O



29

N3



Figure 4.6 Highly potent taxol and docetaxel derivatives with C2 modifications.



phenyl group, whereas para-substitution destabilized it. However, it is more likely

that the meta-substitution is beneficial for the C2 benzoate moiety to bind b-tubulin

through enhanced van der Waals interactions with certain amino acid residues, but

the para-substitution sterically disrupts favorable interactions. This finding was

crucial for the development of highly potent new-generation taxoids, which is

discussed in Section 4.5.1.

Recently, based on advanced protein NMR analysis and on molecular modeling, a

number of taxol and docetaxel derivatives were systematically designed, synthesized, and assayed for their binding affinity to microtubules and cytotoxicity [136].

Among those compounds, 29 was found to be the most potent docetaxel derivative

[136], which introduced a meta-azidobenzoyl group at C2 from Kingston

and coworkers’ SAR study [134] and a propanoyl group at C10 from Ojima’s SAR

study [137]. Compound 29 showed excellent cytotoxicity against taxol-resistant

MDR cancer cell lines, indicating that Pgp-mediated drug resistance could be

circumvented by developing taxanes with extremely high binding affinity to

microtubules [136].

Ring C, C6- and C7-Positions (Figure 4.7): Deacetylation and deoxygenation at the

C4-position of taxol led to the loss of activity in the microtubule assembly assay

[138]. In addition, most derivatives with ester, ether, carbonate, and carbamate

linkages at C4 showed diminished cytotoxicity against several cancer cell lines

[133]. Among the C6-substituted taxol analogs, compound 30a was twofold to

threefold more cytotoxic than taxol in vitro, whereas 30b was much less active [139].

6a-Hydroxytaxol is a known metabolite of taxol excreted from the bile [139]. Thus,

C6-halogenated derivatives 30c–30e were synthesized to block this metabolic

pathway. The potencies of these compounds in vitro (tubulin, HCT-116 human

colon cancer cell line) and in vivo (murine M109 lung carcinoma xenograft) were

very similar to that of taxol, and no significant metabolite formation by human liver

microsomes was observed, indicating that C6 a-halogenation effectively blocked

this metabolism [140]. The C4–C6-bridged macrolactone analog 31 was found

inactive in the tubulin-assembly assay and three orders of magnitude less potent

against MCF7 and PC3 cell lines compared to taxol [141]. The 7a-fluorotaxol (32)



137



138



4 Taxol, Taxoids, and Related Taxanes

OH



O



AcO

O

Ph



NH

Ph



O



Ph



O



AcO



NH



NH



F



32



Ph



O



AcO



O

NH



AcO



O

Ph



OH



O



NH



OH



33



OCH2SMe



OH



Ph



Ph



O

OH



35

larotaxel

O



AcO



O



O



O



NH O



34

BMS-184476



O



AcO



O



O



H

OH O OAc

O

Ph



OCONH-PEG



O



H

OH O OAc

O

Ph



O



O

O



O



O



Ph



O



Ph



O



O



31



H

OH O OAc

O

Ph



O



H

OH O O

O

Ph O



O

OH



O



Ph



O



O



Ph



O

Ph



O



O



H

O

OH O OAc

OH

O

Ph

30

a: R = N3; b: NH2

c: Cl; d: F; e: Br



OH



O



AcO



O



R



H

OH O OAc

O

Ph



O



T



O

T



NH



O



Ph



O

OH



O

H

OH O OAc

O

25b

Ph



O



Figure 4.7 Examples of taxol derivatives with modifications in ring C and larotaxel.



was comparable to, but less potent than, taxol against HCT-116 colon carcinoma

cells, as well as in the tubulin polymerization assay [142].

A good number of C7-modified prodrugs have been synthesized and some

examples are discussed in Section 4.3.2.3. The IC50 values of highly water-soluble

taxol derivatives with 7-polyethylene glycol (PEG350-5000) carbamates 33 against

P388 murine leukemia cell line in vitro were 2–3 orders of magnitude less than

taxol [143]. The C7 methylthiomethyl ether, BMS-184476 (34), exhibited excellent in

vivo activity against the taxol-resistant HOC79 ovarian tumor xenograft, and

advanced to human clinical trials [144]. A C7-modified taxoid bearing fused

cyclopropane moiety at C7–C8, larotaxel (35) is currently in phase II clinical trials



4.3 Structure---Activity Relationships (SAR) of Taxol



OH



O



O



OH



O



O

OH



R



NH



O



OH



OH

O



O



H

OH O O



O



O



36

a: R = Ph

b: R = t-BuO



NH



O



R1



O

OH



O



139



H

OH O O

O



37 (R1 = i-Bu)

37a = IDN5390

38 (R1 = i-butenyl)



R2



O

O



a: R2 = H

b: R2 = OMe

c: R2 = Cl

d: R2 = F



Figure 4.8 C-seco-taxoids.



[145], and its clinical development is discussed in Section 4.6.3. The unique

cyclization of the C19 methyl group to C7 was discovered upon treatment of the 7aOH epimer of taxol with diaminosulfur trifluoride [146]. Photoreactive taxol-analog

25b bearing benzophenone and tritium-labeled ethylene moieties at C7 is a very

useful photoaffinity labeling agent [147] that identified a single amino acid residue

(Arg282) in the taxol binding site of b-tubulin [148], and was used to map the taxol

binding region in the P-glycoprotein [129].

Ring C, C-seco-Taxoids (Figure 4.8): Appendino synthesized C-seco analogs of taxol

(36a) and docetaxel (36b), which showed 2 and 1 order of magnitude diminished

cytotoxicity, respectively, than taxol against MDA-MBA321 breast cancer cell line

[149]. However, C30 -modified new-generation C-seco-taxoid, IDN5390 (37a), was

found to exhibit substantially higher potency than taxol against extremely taxolresistant human ovarian adenocarcinoma cell lines, A2780TC1 and A2780TC3

[149,150]. These cell lines overexpress class III b-tubulin without significant

changes in the levels of class I, Iva, and IVb b-tubulins [150–152]. Several C2modified IDN5390 analogs 37b–37d were synthesized and their cytotoxicity against

these taxol-resistant cancer cell lines evaluated [153]. Among these analogs, 37b

exhibited the highest potency against the A2780TC3 cell line, although all three

analogs showed two orders of magnitude and 5–11 times higher potency than taxol

and IDN5390, respectively [153]. Also, C30 -isobutenyl C2-modified analogs 37a–37d

were synthesized and their potency evaluated. These C-seco-taxoids showed more or

less comparable potency to that of 37b–37d, but 37c was the most active against the

A2780TC1 cell line, showing 13 times higher potency than taxol [153].

Ring D (Figure 4.9): It was hypothesized that the oxygen atom in ring D would act

as a hydrogen bond acceptor and also lock the taxane skeleton in a conformation

critical for its binding to tubulin [119,138,154]. In fact, D-seco analogs synthesized

by Georg and coworkers were found to be much less active than taxol [155], and the

1

H-NMR analysis suggested that these D-seco analogs adopted a different

conformation from that of taxol [126,156].

D-ring-modified taxol analogs 39 and 40, in which the O-atom is replaced with

nitrogen, sulfur, and selenium, exhibited markedly reduced activity in the tubulin

polymerization and cytotoxicity assays [157,158]. In contrast, the D-ring-modified

analog 41, wherein the oxetane skeleton was replaced with a cyclopropane ring, was



140



4 Taxol, Taxoids, and Related Taxanes



O



AcO



O

NH



O



OH



O



AcO



O

O



NH



NH



Ph



O



H

OH O OAc

OH

O

39

Ph

a: R = Bn

b: H = H



Ph



AcO



O



O



N R



O



OH



O



H

OH O OR

OH

O

40

a: X = S; R = OCOMe Ph



Ph



O



X



b: X = Se; R = H



OH



O



Ph



O

OH

41



H

OH O OAc

O

Ph



Figure 4.9 D-ring-modified taxol and docetaxel analogs with oxetane isosteres.



found to retain strong cytotoxicity (about half as that of taxol against several cancer

cell lines) and comparable activity in the microtubule disassembly inhibitory assay

[159]. Thus, it was concluded that the major function of the oxetane ring should be

to rigidify the C-ring to keep the bioactive conformation of taxol skeleton for

tubulin binding, but the oxygen of the D-ring is likely to participate in

strengthening the tubulin binding [159].

4.3.2.3 Prodrugs of Taxol

The C20 - and C7-positions have been extensively exploited for the development of

prodrugs of taxol (Figure 4.10). C20 -prodrugs 42–44 showed enhanced aqueous

solubility and improved antitumor activity [160]. For example, 44 acted as an

efficacious prodrug at 40 and 20 mg/kg, causing complete remissions of MX-1

breast cancer xenograft in all surviving animals [160]. “Protaxols” 45–47 were found

stable at neutral pH at room temperature, but readily hydrolyzed under basic

conditions to release taxol [161]. The first tumor-directed conjugate of taxol,

PTXPEGBBN [7–13], employed the 7–13 heptapeptide fragment of bombesin

(BBN) [7–13] as the tumor-directed moiety, which was conjugated to the C20 position of taxol by a PEG linker [162]. The IC50 of this conjugate against

NCI-H1299 human NSCLC cell line was 2.5 times better than the free drug, that is,

taxol [162].

C7 prodrugs of taxol, bearing PEG-glucuronide [163], PEG-glycinate [164], and

PEG-HSA [165], were synthesized and their efficacy examined. These C7 prodrugs

exhibited reduced blood clearance, as well as reduced accumulation in liver and

spleen, leading to promising efficacy in vivo. The C7-glyceroyl carbonate derivative

of taxol, Protaxel (48), was 50 times more water soluble and had 2.5-fold higher

maximum tolerated dose (MTD) than that of taxol [166]. Protaxel possessed

reduced toxicity to hematopoetic stem cells by 100-fold, while retaining comparable



4.4 Structural and Chemical Biology of Taxol



ONa



O



O



R=

AcO



O

Ph



NH



O



O



OH



O



Ph



O

OR



H

OH O OAc

O

Ph



O



O



AcO



O



O



n

43



O



44



O



R=

O



OH



S



OH



3

46

N



H



O



O

S

O

47



Cl



O



O

OH



O



O



Ph



O



OH



ON

H



OR



H

OH O OAc

O

Ph



OH



45



O

NH



O



H

N

O



Ph



42

O



141



O

O



O



OH



O



N

H



OH

48



49

H2N



Figure 4.10 Prodrugs derived from taxol with modifications at C2 and C7.



activity to taxol in vitro against a number of cancer cell lines, and also exhibited

superior efficacy to taxol in vivo against human cancer xenografts, PC-3, OVCAR-3,

and MDA-MB-469 [166]. BMS developed several C7 dipeptide (Phe–Lys) conjugates, designed to be cleaved by cathepsin B. For example, C7-prodrug 49

conjugated to a Boc–Phe–Lys moiety via a self-immolative p-aminobenzylcarbonyl

spacer was synthesized, which showed excellent plasma stability and good rates in

taxol release with cathepsin B and rat liver lysosomes [167].



4.4

Structural and Chemical Biology of Taxol

4.4.1

Bioactive Conformation of Taxol



Initial studies on the possible bioactive conformation of taxol were focused on the

solution-phase conformations studied by NMR spectroscopy. Two major conformers were found, the prevalence of each depended on the polarity of the solvent. In

nonpolar solvents, such as chloroform, it was found that the N-benzoylphenylisoserine conformation at C13 was fixed by a network of hydrogen bonding between

the C10 carbonyl, C20 hydroxyl, and C30 NH groups [168]. This conformation is

similar to the X-ray crystal structure of docetaxel [169,170]. However, in polar

solvents such as aqueous methanol, taxol was found to adopt the “hydrophobic

collapse” conformation, wherein the C2 and C30 phenyl rings and the C30 Nbenzoyl group formed a hydrophobic cluster, arranging hydrophilic groups in the



Ph

H

N

O



NH-Boc



142



4 Taxol, Taxoids, and Related Taxanes



AcO



O

NH

F



O

O



O

HO

H



OH



F



AcO



O



O



19



19



O OH



NH



O



O

O



O



O



OAc



HO



OH



19



F



O



O OH



H



O



OAc

O



50b



50a



19



AcO



O

C15



O OH



O



13



NH O

C



F

AcO



NH



13



O



O



O

HO



OH



O



OAc

O



O OH



O

2H



HO



OH



O



O

O



O

O

C(2H)3



50d



50c

19



F



19



F



Figure 4.11 Fluorine probes used to study the bioactive conformations of taxol.



outer sphere of the molecule [135]. Conformationally restricted macrocyclic taxol

analogs were designed and synthesized, mimicking these two conformations of

taxol, but none of the analogs retained the activity of taxol, suggesting that neither

was the bioactive microtubule-bound conformation [171].

Difluorotaxol (50a) was designed and synthesized as a “fluorine probe” to study

the solution structures and dynamic behavior of taxol and docetaxel molecules by

means of variable temperature 19F-NMR in combination with conformational

analysis of the phenylisoserine moiety by 1H-NMR and the 1 H À 19 F hetero-NOE

2D NMR techniques (Figure 4.11) [172]. This study led to the identification of a

third solution-phase conformer, which was the major conformation at ambient

temperature and was supported by a restrained molecular dynamics analysis,

showing a substantial stabilization of this conformation in protic solvents [172].

Difluorodocetaxel (50b) served as a fluorine probe to investigate the bioactive

conformation of docetaxel bound to microtubules in the solid state by MAS solidstate 19F-NMR using the RFDR (radio frequency-driven recoupling) technique.

These studies accurately determined the 19F–19F distance in the molecule,

providing a solid basis for molecular modeling and conformational analysis

(Figure 4.11) [118].



In 1998, the first tubulin-bound structure of taxol was reported at 3.7 A

resolution. The structure was obtained using the cryo-electron microscopy (cryoEM or electron crystallography) of Zn2ỵ-stabilized a,b-tubulin dimers [173] with

the help of two photoaffinity labeling studies on microtubules that identified the

1–31 and 217–233 amino acid residues, respectively, in the b-tubulin subunit

[174,175]. Since then, the b-tubulin-bound structure of taxol, a model for

microtubule-bound taxol structure, was extensively studied using solid-state NMR



4.4 Structural and Chemical Biology of Taxol



analysis [176,177], computational analyses [177–181], and the synthesis of

conformationally restrained macrocyclic taxol analogs [179,182–184].

An extremely site-selective photoaffinity probe, {3 H}2-7-(benzoyldihydrocinnamoyl)-taxol (25b, Figure 4.7), succeeded in identifying the single amino acid

residue, Arg-282 [148] in the b-tubulin subunit of microtubules, which made a

sharp contrast to the previous two photoaffinity labeling results mentioned above.

This result, using real microtubules, was critical to validate the positioning of the

baccatin skeleton in the cryo-EM structure using the Zn2ỵ-stabilized a,b-tubulin

dimer model.

The most valuable information about the microtubule-bound taxol structure was

provided by the MAS solid-state NMR using the REDOR (rotational-echo doubleresonance) pulse sequence for distance measurement [185]. Kingston and coworkers used {19 F, 13 C, 15 N} triply labeled taxol derivative 50c for the REDOR

experiment and successfully determined two 13 C À 19 F distances in the microtubule-bound state (Figure 4.11) [176]. Based on these two distances, extensive

molecular modeling and molecular dynamics studies were performed to generate

two possible bioactive taxol structures, that is, “T-taxol” and “REDOR-taxol”

structures [178,179].

These two structures have been further refined based on the second REDOR

experiment results using {19 F, 2 H}-labeled taxol derivative 50d to determine three

more intramolecular atom–atom distances between 19 F and deuterium (Figure 4.11) [177], as well as the use of computationally optimized higher resolution

coordinates (1JFF) for the b-tubulin-bound taxol crystal structure [186]. The refined

“T-taxol” and “REDOR-taxol” structures are shown in Figure 4.12 [181]. These two



Figure 4.12 Proposed microtubule-bound structures of taxol: “T-taxol (a) and “REDORtaxol” (b) [181].



143



144



4 Taxol, Taxoids, and Related Taxanes



structures differ in the orientation of the C20 OH group. In “REDOR-taxol,” the C20

OH forms a hydrogen bond with the nitrogen of His229 [181], whereas the C20 O

interacts with the HN moiety of Gly370 in “T-taxol” [178,181]. To support these two

structures, conformationally constrained macrocyclic taxol analogs were designed,

synthesized, and evaluated for their biological activities.

The C4–C30 Ph-linked macrocyclic taxol analogs, 51a and 51b, designed based on

“T-taxol,” exhibited substantially higher cytotoxicity (2–20 times) to taxol against

PC3 and A2780 cell lines and were more potent (1.5–2 times) than taxol in the

tubulin polymerization assay (Figure 4.13) [182,183]. On the other hand, the

C1–C30 N-Bz-linked macrocyclic taxol analogs, 52a and 52b, designed and

synthesized based on “REDOR-taxol,” exhibited virtually the same activity as that of

taxol in the tubulin polymerization assay (Figure 4.13) [179,184]. Analog 52b

exhibited equipotent cytotoxicity against six human cancer cell lines, MCF7, NCIADR, LCC6-WT, LCC6-MDR, HT-29, and A2780 [184].

The molecular dynamics simulations of 51a, 51b and 52a, 52b showed that 51a,

51b could easily take the “REDOR-taxol” conformation with a very stable hydrogen

bonding between C20 OH and His229, whereas the hydrogen bonding between C20

O and Gly370 was found to be very weak and unstable. The Monte Carlo structural

search of these macrocyclic taxol analogs suggests that both proposed bioactive

structures of taxol still need further refinement [184].



AcO



O



AcO



O OH



O



O



O

HO



HO

O



OBz O



O



O

HO



HO

O



O



N

H



O



51b



O OH



AcO



O

HN

O



O OH



O

O



OH



OBz O



N

H



51a



AcO



O OH



H

OAc

O HO OBz



52a



O



HN

O



O

OH



H

OAc

O HO OBz



O



52b



Figure 4.13 Macrocyclic taxol analogs designed based on the “T-taxol” and “REDOR-taxol”

structures.



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