An increasingly competitive pharmaceutical market demands improvement in the efficiency and probability of drug candidate discovery. Usually these new drug candidates are targeted for oral administration, so a detailed understanding of the molecular-level properties that relate to optimal pharmacokinetics is a critical step toward improving the probability of selecting successful clinical candidates. Although the characteristics of druglike molecules have been previously discussed in the literature, the importance of this topic sustains a continued interest for additional perspective and further detailed statistical analyses. In this contribution, we approach the analysis from the perspective of profiling distinguishing features of orally administered drugs. We have compiled both structural and route-administration information for a total of 1729 marketed drugs to provide a solid basis for developing a new perspective on the characteristics of over 1000 orally administered drugs. The molecular properties and most commonly occurring structural elements are statistically analyzed to capture the differences between routes of administration, as well as between marketed drugs and SAR or clinical compounds. We find that, with respect to other routes of administration, oral drugs tend to be lighter and have fewer H-bond donors, acceptors, and rotatable bonds than drugs with other routes of administration. These differences are particularly pronounced when comparing the mean values for oral vs injectable drugs. We also demonstrate that the mean property values for oral drugs do not vary substantially with respect to launch date, suggesting that the range of acceptable oral properties is independent of synthetic complexity or targeted receptor. Finally, we note that, while these properties are descriptive of each class, they are not necessarily predictive of what class any particular drug will reside in, since there is significant overlap in the acceptable ranges found for each drug class.

A new class of 16-membered macrolides, the epothilones (Epos), has been synthesized and evaluated for antitumor potential in vitro and in vivo. Recent studies in these and other laboratories showed that epothilones and paclitaxel (paclitaxel) share similar mechanisms of action in stabilizing microtubule arrays as indicated by binding-displacement studies, substitution for paclitaxel in paclitaxel-dependent cell growth, and electron microscopic examinations. The present study examined cell growth-inhibitory effects in two rodent and three human tumor cell lines and their drug-resistant sublines. Although paclitaxel showed as much as 1,970-fold cross-resistance to the sublines resistant to paclitaxel, adriamycin, vinblastine, or actinomycin D, most epothilones exhibit little or no cross-resistance. In multidrug-resistant CCRF-CEM͞VBL 100 cells, IC 50 values for EpoA (1), EpoB (2), desoxyEpoA (3) (dEpoA), desoxyEpoB (4) (dEpoB), and paclitaxel were 0.02, 0.002, 0.012, 0.017, and 4.14 M, respectively. In vivo studies, using i.p. administration, indicated that the parent, EpoB, was highly toxic to mice and showed little therapeutic effect when compared with a lead compound, dEpoB. More significantly, dEpoB (25-40 mg͞kg, Q2Dx5, i.p.) showed far superior therapeutic effects and lower toxicity than paclitaxel, doxorubicin, camptothecin, or vinblastine (at maximal tolerated doses) in parallel experiments. For mammary adenocarcinoma xenografts resistant to adriamycin, MCF-7͞ Adr, superior therapeutic effects were obtained with dEpoB compared with paclitaxel when i.p. regimens were used. For ovarian adenocarcinoma xenografts, SK-OV-3, dEpoB (i.p.), and paclitaxel (i.v.) gave similar therapeutic effects. In nude mice bearing a human mammary carcinoma xenograft (MX-1), marked tumor regression and cures were obtained with dEpoB.

The epothilones are naturally occurring, cytotoxic macrolides that function through a paclitaxel (Taxol)-like mechanism. Although structurally dissimilar, both classes of molecules lead to the arrest of cell division and eventual cell death by stabilizing cellular microtubule assemblies. The epothilones differ in their ability to retain activity against multidrug-resistant ( Paclitaxel (Taxol**), Fig. 1, is currently used as the front-line therapeutic agent in a variety of solid forms of cancer including ovarian, breast, colon, lung, and liver neoplasms (1). Acquired resistance to paclitaxel and other commonly used cancer chemotherapy agents may be mediated by a number of mechanisms, including overexpression of the energy-dependent drug-transport protein P-glycoprotein (ref. 2, and references therein). Broad-spectrum resistance to structurally and mechanistically diverse anticancer agents constitutes the multidrugresistance (MDR) phenotype. A search for paclitaxel analogues with improved performance in vitro and in vivo has met with limited success (3, 4), although certain MDR reversal agents appear promising when coadministered with the anticancer agent (5).Although the 16-membered ring structure of the epothilones bears little structural resemblance to paclitaxel, the two agents share a common cellular mechanism of action (6-8). Both the epothilones and paclitaxel exert their biological effects by stabilizing microtubule assemblies, thus leading to the arrest of cell division and eventual cell death. By far the most intriguing property of the epothilones at the in vitro level is their lack of cross resistance to MDR cell lines when compared with major antitumor agents, including paclitaxel, vinblastine, adriamycin, camptothecin, and etoposide, all of which are currently used in clinical settings (6-9). The epothilones are also more watersoluble (6, 10-12) and more readily available through chemical synthesis (6,(13)(14)(15)(16)(17)(18)(19)(20) than is paclitaxel. The solubility advantage could allow for less cumbersome administration and increased bioavailability of the chemotherapy agent than paclitaxel. The synthetic advantage would be useful in generating epothilone congeners more advantageous than the natural product.We recently reported that Z-12,13-desoxyepothilone (dEpoB; Fig. 1), a synthetic intermediate en route to epothilone B, † † demonstrated promising activity both in vitro and in murine models harboring tumor xenografts (6, 21). In the previous report, we also showed that dEpoB was Ͼ35,000-fold more potent than paclitaxel in inhibiting cell growth of DC-3F͞ADX in vitro. During the earlier in vivo pharmacologic evaluations of the epothilones, both dEpoB and paclitaxel were administered with dimethyl sulfoxide (DMSO) as a solvent by using i.p. injection (6,22). However, i.v. administration is more appropriate for paclitaxel than for dEpoB, resulting in higher efficacy and lower toxicity. Because the primary focus of this research was to compare dEpoB and paclitaxel, we adjusted the administ...

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Studies into the use of samarium diiodide (SmIz) in the reductive elimination of 1,a-acetoxy sulfones and the reductive cleavage of vinyl sulfones are reported. Parallel investigations with sodium/ mercury, amalgam ( N a g ) revealed over-reduction in several cases in which the desired products were heavily conjugated or conjugated to an aromatic moiety. A mechanistic study revealed some of the intricacies of the SmIz-promoted Julia-Lythgoe olefination. The classical N a g reductive method was also examined, and an alternative mechanism is proposed. Observations described herein provide important insights into the mechanism and synthetic utility of these methods. The optimum protocol developed utilizes SmIz reduction of vinyl sulfones in the presence of DMPU and MeOH and gives generally high yields with good to excellent E stereoselectivity.

The stabilization of the transition state through a favorable interaction between the double bond of 1 and the carbonyl group of 2 appears to be responsible for the high diastereoface selectivity of the aldol reaction. This key step in the highly concise total synthesis of epothilone B is followed by a Suzuki coupling to introduce the thiazole domain, a Noyori reduction to control the stereochemistry at C3, and a final macrolactonization (see reaction scheme). X=protecting group.

Intramolecular Lewis acid-promoted cyclization reactions of both (Z)-and (£)-3-phenyl-8-(tri-«butylstannyl)oct-6-enal and (Z)-and (£)-3-(benzyloxy)-8-(tri-n-butylstannyl)oct-6-enal have been examined using a variety of Lewis acids, specifically BF3*Et20, CF3CO2H, SnCL, TiCLt, and MgBr2. Thermally promoted cyclizations were also examined. The results show that product stereochemistry is a sensitive function of both olefm stereochemistry and Lewis acid. The data acquired in these studies also suggest that such reactions are mechanistically more complex than previous studies with more constrained systems have revealed.

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