Oh

Figure 39 Taxane SAR.

Figure 40 Structures of clinically relevant taxanes.

peripheral functionality is required. Notable exceptions to this rule are the aryl side chains, in which some variability is permitted, and the carbonyl, which may be reduced.

With the growing clinical use of paclitaxel, P-gp-based MDR emerged as a factor that could limit the clinical utility of the drug. Furthermore, the formulated drug product showed both drug- and formulation-related toxicities, including neuropathy and allergic reactions. Analog work to address these issues resulted in the identification of orataxel 85, an orally active taxane, structurally similar to docetaxel 86, that shows potency not only against wild-type cancers, but also P-gp expressing cancers. This compound showed excellent pharmacological properties preclinically and has advanced to clinical trials.193 In addition to its improved activity against taxol-resistant tumors, because of its high level of oral bioavailability, this compound does not require the clinically cumbersome cremaphore-based formulation used by other taxanes.

Although there is considerable use of taxanes for a range of indications, commanding the lion's share of the market, and generating combined yearly sales of nearly 2 billion dollars, the high toxicity and poor solubility of these drugs may ultimately limit their utility. In addition, these compounds are substrates for P-gp, a transmembrane efflux pump that serves to limit the intracellular concentration of drug substrates in cells. Thus, tumor cells that express P-gp are resistant to taxanes and other hydrophobic drugs that are substrates for the efflux pump. These issues combine to create an opportunity for new taxanes and other drugs, free of these liabilities, to enter the market and gain acceptance.194

7.04.3.2 Epothilones

Of the new microtubule stabilizers, the epothilone class is by far the most advanced clinically. Epothilones A 87 and B 88 were isolated from the myxobacterium Sorangium cellulosum and originally identified due to their antifungal activity.195 The potent antitumor properties and the elucidation of the microtubule-stabilizing effect of these compounds heightened interest in the epothilones.196 As well as epothilones A and B, the culture of the producing organism also yields a wide variety of other epothilone-related structures, including epothilones C, D 89, and F 90.197 In addition to these major natural products, a number of totally synthetic and semisynthetic analogs have been prepared and studied in vitro.198-202

The SARs that emerge from this body of work are shown in Figure 41. In general, the macrocycle can be divided into two halves for the purposes of discussing the SAR. The C-1 to C-8 region of the molecule is highly sensitive to modification, with even modest changes abrogating activity. In contrast, the C-9 to C-17 portion affords a greater degree of flexibility. In various forms, epoxide isosteres, small heterocycles, as well as alkyl substituents, may be substituted in the C-12 to C-13 region with modest or no reduction in activity. Likewise, compounds containing a range of side chains emanating from C-15 have been found to maintain varying degrees of activity (Figure 42).

To date, seven epothilone analogs have entered human clinical trials. Compound 88 entered phase II clinical trials in 2002. Likewise, the semisynthetic lactam analog of epothilone B, BMS-247550 91, was advanced to phase III in 2004. The synthesis of this material, prepared in a three-step, one-pot procedure from 88, was presumably motivated by its more secure patent position and the possibility for it to show reduced hydrolytic instability as compared to the natural product. In 2004, epothilone D (named KOS-862) 89, entered phase II human clinical trials. Interestingly, in a head-to-head comparison with 88, the in vivo toxicity of 89 in mice was found to be as much as 40-fold lower. A recent epothilone analog to enter the clinic is BMS-310705, the 21-amino analog of epothilone B 88. Two epothilone analogs prepared by total chemical synthesis have entered human clinical trials. KOS-1584 94, the 9,10-dehydro analog of KOS-862, and ZK-epo 95 entered phase I human clinical trials in late 2004. Interestingly, the C-6 allyl moiety present in ZK-epo is an exception to the otherwise tight SAR in this region of the molecule. This compound does, however, take advantage of the observation that the side-chain substitution is well tolerated. Methylthio analog 93 was also recently advanced into clinical study.

Aryl analogues ACTIVE

Aryl analogues ACTIVE

Epoxide isosteres, small rings and small alkyl groups TOLERATED

Modest structural changes DIMINISH/ABOLISH activity

Epoxide isosteres, small rings and small alkyl groups TOLERATED

Modest structural changes DIMINISH/ABOLISH activity

Figure 41 Epothilone SAR.

Figure 41 Epothilone SAR.

The epothilones that have advanced to the clinic have undergone extensive preclinical evaluation.204 The compounds all show excellent potency in cell culture against a range of susceptible and MDR-expressing resistant cell lines. Although much of the information regarding the clinical behavior of this class of compounds has only appeared in poster or abstract form, the clinical prospects of the class appear good.205

7.04.3.3 Discodermolide

Discodermolide 96 (Figures 43 and 44) was isolated from the deep-water sponge Discodermia dissoluta by Gunasekera and co-workers.206 Initial biological tests indicated that discodermolide has immunosuppressive activity, while recent interest has focused on its potent antimitotic activity. Notably, 96 has been reported to show potent activity against MDR carcinoma cell lines, due to its reduced affinity for the P-gp efflux pump.207 It is thought to be c. 100-fold more soluble in water than paclitaxel and thus is likely to be more easily formulated.

The natural source of disocdermolide does not provide sufficient material for advanced evaluation, with the reported isolated yield of 7 mg from 434 g of frozen sponge. At this time, the only reliable source of meaningful quantities of the natural product is total chemical synthesis. Total syntheses of 96 have been reported by several groups.208-213 A detailed discussion of these syntheses has been published.214

This synthetic effort has resulted in the production of sufficient material to serve as the foundation for a phase I dose escalation clinical trial of discodermolide, which began in 2002. This clinical trial was suspended when 3 patients receiving 14.4-19.2 mgm_ 2 q3w experienced, after the fourth cycle of therapy, interstitial pneumonitis that proved fatal.215 In this clinical study, it was also noted that the pharmacokinetics of discodermolide suggest that it is subject to hepatobiliary recirculation.

From analogs obtained by synthesis and semisynthesis, an in vitro discodermolide SAR is now emerging. Poly-acetylated versions of the compound show a range of activity.216 Totally synthetic analogs, in which methyl groups at either C-16217 or C-14 have been deleted, retain activity, as does the 2,3-dehydro analog.218 Analogs of 96 in which the C-1 lactone cabonyl has been reduced and stored as the thiophenyl acetal show activity similar to the natural product. The retention of activity by analogs in which the lactone ring has been modified suggest that this region of the molecule may be a fruitful area for further analog work. A recent series of publications describes the replacement of the

Figure 43 Structures of discodermolides.

Figure 43 Structures of discodermolides.

C-1 to C-8 region of the molecule with dramatically simplified structures, for example 97, resulting in compounds that are in some cases fivefold more potent in vitro.219-222 One group has prepared in excess of 50 discodermolide analogs by total synthesis and has indicated that certain isosteres of the C-21 to C-24 diene maintain potency while substitution of the C-13 to C-15 carbon atoms with an N-methyl amide abolish activity.223

7.04.3.4 Other Natural Products

Eleuthrobin 99 (Figure 45) and the structurally related sarcodictyins 100 and 101 are marine natural products that were identified as cytotoxins.224,225 The unique structure of these compounds and their antiproliferative activity initially made them quite attractive to the synthetic and medicinal chemistry community. These compounds have been synthesized and a number of analogs have been prepared and studied in vitro as potential anticancer agents. Like the taxanes, these compounds were found to be substrates for P-gp and hence show dramatically reduced cytotoxicity against MDR-expressing cell lines. The SAR of the eleuthrobin/sarcodictyin class of microtubule-stabilizing agents has been explored in a combinatorial fashion.226 This effort led to the conclusion that the conserved urocanic acid side chain was required for activity and that acetal and ester variants (R1 and R2 in 100 and 101) were more easily tolerated. Although these compounds showed early promise as novel antiproliferative agents, the failure of this class to address adequately resistant tumor lines suggests that it is unlikely that it will yield clinically useful cytotoxins.

The microtubule-stabilizing macrocyclic lactone laulimalide 102 (Figure 46), also known as fijianolide, has been reported in small quantities from a number of different sponge species.227-229 This compound is quite unstable at low pH and undergoes a rapid conversion to isolaulimalide 103 via displacement of the epoxide by the C-20 alcohol with concomitant loss in potency. Despite its promise as an antiproliferative agent, the in vivo evaluation of laulimalide has not yet been described, presumably due to lack of material for such experiments. Not surprisingly, laulimalide has been the

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