KRAS pathway expression changes in pancreatic cancer models by conventional and experimental taxanes.

The KRAS signalling pathway is pivotal for pancreatic ductal adenocarcinoma (PDAC) development. After the failure of most conventional cytotoxic and targeted therapeutics tested so far, the combination of taxane nab-paclitaxel (Abraxane) with gemcitabine recently demonstrated promising improvements in the survival of PDAC patients. This study aimed to explore interactions of conventional paclitaxel and experimental taxane SB-T-1216 with the KRAS signalling pathway expression in in vivo and in vitro PDAC models in order to decipher potential predictive biomarkers or targets for future individualised therapy. Mouse PDAC PaCa-44 xenograft model was used for evaluation of changes in transcript and protein levels of the KRAS signalling pathway caused by administration of experimental taxane SB-T-1216 in vivo. Subsequently, KRAS wild-type (BxPc-3) and mutated (MiaPaCa-2 and PaCa-44) cell line models were treated with paclitaxel to verify dysregulation of the KRAS signalling pathway gene expression profile in vitro and investigate the role of KRAS mutation status. By comparing the gene expression profiles, this study observed for the first time that in vitro cell models differ in the basal transcriptional profile of the KRAS signalling pathway, but there were no differences between KRAS mutated and wild-type cells in sensitivity to taxanes. Generally, the taxane administration caused a downregulation of the KRAS signalling pathway both in vitro and in vivo, but this effect was not dependent on the KRAS mutation status. In conclusion, putative biomarkers for prediction of taxane activity or targets for stimulation of taxane anticancer effects were not discovered by the KRAS signalling pathway profiling in various PDAC models.

Hedgehog pathway overexpression in pancreatic cancer is abrogated by new-generation taxoid SB-T-1216.

The Hedgehog pathway is one of the major driver pathways in pancreatic ductal adenocarcinoma. This study investigated prognostic importance of Hedgehog signaling pathway in pancreatic cancer patients who underwent a radical resection. Tumors and adjacent non-neoplastic pancreatic tissues were obtained from 45 patients with histologically verified pancreatic cancer. The effect of experimental taxane chemotherapy on the expression of Hedgehog pathway was evaluated in vivo using a mouse xenograft model prepared using pancreatic cancer cell line Paca-44. Mice were treated by experimental Stony Brook Taxane SB-T-1216. The transcript profile of 34 Hedgehog pathway genes in patients and xenografts was assessed using quantitative PCR. The Hedgehog pathway was strongly overexpressed in pancreatic tumors and upregulation of SHH, IHH, HHAT and PTCH1 was associated with a trend toward decreased patient survival. No association of Hedgehog pathway expression with KRAS mutation status was found in tumors. Sonic hedgehog ligand was overexpressed, but all other downstream genes were downregulated by SB-T-1216 treatment in vivo. Suppression of HH pathway expression in vivo by taxane-based chemotherapy suggests a new mechanism of action for treatment of this aggressive tumor.

Novel T9 loop conformation of filamenting temperature-sensitive mutant Z from Mycobacterium tuberculosis.

As of 2017, tuberculosis had infected 1.7 billion people (23% of the population of the world) and caused ten million deaths. Mycobacterium tuberculosis (Mtb) is quickly evolving, and new strains are classified as multidrug resistant. Thus, the identification of novel druggable targets is essential to combat the proliferation of these drug-resistant strains. Filamenting temperature-sensitive mutant Z (FtsZ) is a key protein involved in cytokinesis, an important process for Mtb proliferation and viability. FtsZ is required for bacterial cell division because it polymerizes into a structure called the Z-ring, which recruits accessory division proteins to the septum. Here, the crystal structure of the MtbFtsZ protein has been determined to 3.46 Šresolution and is described as a dimer of trimers, with an inter-subunit interface between protomers AB and DE. In this work, a novel conformation of MtbFtsZ is revealed involving the T9 loop and the nucleotide-binding pocket of protomers BC and EF.

Effects of orally active taxanes on P-glycoprotein modulation and colon and breast carcinoma drug resistance.

BACKGROUND: The taxane paclitaxel (Taxol) is often of limited efficacy in chemotherapeutic regimens because some cancer cells express high levels of the efflux pump, P-glycoprotein (Pgp), which removes the drug from the cells. The orally active paclitaxel analog IDN-5109 has been reported to overcome Pgp-mediated drug resistance. We tested whether IDN-5109 acts by modulating Pgp activity. METHODS: Human MDA435/LCC6mdr1 and MDA435/LCC6 breast carcinoma cells, which express and do not express Pgp, respectively, were incubated with [3H]IDN-5109 and paclitaxel to determine intracellular drug accumulation. Flow cytometry was used to analyze intracellular retention of two Pgp substrates, rhodamine 123 (Rh-123) and doxorubicin, in both breast carcinoma cell lines and in human colon carcinoma cells (SW-620, DLD1, and HCT-15, whose Pgp levels vary) treated with different taxanes. The effects of IDN-5109 and paclitaxel on tumor growth in vivo were studied with the use of tumors established through xenografts of Pgp-expressing SW-620 and DLD1 cells in severe combined immunodeficiency mice. All statistical tests were two-sided. RESULTS: Pgp-expressing cells treated with IDN-5109 or with the taxane-based drug resistance reversal agent tRA96023, which blocks Pgp activity, retained 8.1- and 9.4-fold more Rh-123 (P =.0001), respectively, and 1.7- and 1.9-fold more doxorubicin (P =.001), respectively, than cells treated with paclitaxel. Non-Pgp-expressing cells treated similarly demonstrated no increased retention of either substrate. MDA435/LCC6mdr1 cells retained 5.3-fold more [3H]IDN-5109 than [3H]paclitaxel after 2 hours (P =.01). IDN-5109 showed statistically significantly higher tumor growth inhibition than paclitaxel against the SW-620 xenograft (P =.003). CONCLUSIONS: IDN-5109 modulates Pgp activity, resulting in superior tumor growth inhibition against Pgp-expressing tumors as compared with paclitaxel. IDN-5109 may broaden the spectrum of taxane use to include colon tumors.

Hydrogel microstructure live-cell array for multiplexed analyses of cancer stem cells, tumor heterogeneity and differential drug response at single-element resolution.

Specific phenotypic subpopulations of cancer stem cells (CSCs) are responsible for tumor development, production of heterogeneous differentiated tumor mass, metastasis, and resistance to therapies. The development of therapeutic approaches based on targeting rare CSCs has been limited partially due to the lack of appropriate experimental models and measurement approaches. The current study presents new tools and methodologies based on a hydrogel microstructure array (HMA) for identification and multiplex analyses of CSCs. Low-melt agarose integrated with type I collagen, a major component of the extracellular matrix (ECM), was used to form a solid hydrogel array with natural non-adhesive characteristics and high optical quality. The array contained thousands of individual pyramidal shaped, nanoliter-volume micro-chambers (MCs), allowing concomitant generation and measurement of large populations of free-floating CSC spheroids from single cells, each in an individual micro-chamber (MC). The optical live cell platform, based on an imaging plate patterned with HMA, was validated using CSC-enriched prostate and colon cancer cell lines. The HMA methodology and quantitative image analysis at single-element resolution clearly demonstrates several levels of tumor cell heterogeneity, including morphological and phenotypic variability, differences in proliferation capacity and in drug response. Moreover, the system facilitates real-time examination of single stem cell (SC) fate, as well as drug-induced alteration in expression of stemness markers. The technology may be applicable in personalized cancer treatment, including multiplex ex vivo analysis of heterogeneous patient-derived tumor specimens, precise detection and characterization of potentially dangerous cell phenotypes, and for representative evaluation of drug sensitivity of CSCs and other types of tumor cells.

Recent advances in the new generation taxane anticancer agents.

Recent advances in the design and preclinical evaluations of promising new generation taxane anticancer agents are reviewed in this article. Paclitaxel and docetaxel are two of the most important anticancer drugs today. However, recent reports have shown that treatment with these drugs often encounters undesirable side effects as well as drug resistance. Therefore, it is important to develop new taxane anticancer agents with fewer side effects, superior pharmacological properties, and improved activity against drug-resistant human cancers. Structure-activity relationship (SAR) studies led to the discovery of a series of highly active second-generation taxanes. One of them, "Ortataxel" (SB-T-101131, IDN5109, BAY59-8862), exhibits excellent activity against a variety of drug-sensitive and drug-resistant cancer cell lines, as well as human tumor xenografts in mice. It is orally active and is currently in phase II clinical trials. Photoaffinity labeling of microtubules and P-glycoprotein using photoreactive radiolabeled taxoids has disclosed the drug-binding domain of tubulin as well as Pgp. Together with information on microtubule-bound fluorine-labeled taxoids obtained by solid-state NMR studies, the bioactive conformation of paclitaxel and taxoids appears to emerge. Novel taxane-monoclonal antibody (mAb) immunoconjugates, have shown highly promising results for the tumor-specific delivery and release of an extremely cytotoxic, second-generation taxane. Also, another novel series of second generation taxanes conjugated with n-3 polyunsaturated fatty acids, e.g. decosahexaenoic acid (DHA), has exhibited impressive antitumor activity with minimum general toxicity against the highly drug-resistant DLD-1 human colon cancer xenografts in SCID mice.

Structural significance of the acyl group at the C-10 position and the A ring of the taxane core of paclitaxel for inducing nitric oxide and tumor necrosis factor production by murine macrophages.

The antitumor agent, paclitaxel (Taxol), mimics the actions of lipopolysaccharide (LPS) on murine macrophages (Mphi). Various synthetic analogs of paclitaxel were examined for their potencies to induce nitric oxide (NO) and tumor necrosis factor (TNF) production by murine peritoneal Mphi, and by human peripheral blood cells. The benzoyl group at C-2, the hydroxy group at C-7 and the acetyl group at C-10 were found to be critically important sites to activate murine Mphi. Nor-seco-taxoid analogs lacking the A ring of the taxane core of paclitaxel were inactive, but inhibit paclitaxel- or LPS-induced NO production. All the compounds tested did not induce TNF production by human blood cells.

Tumor specific novel taxoid-monoclonal antibody conjugates.

The basic principle of the targeted delivery approach is that the conjugation of a drug to a tumor-specific molecule renders the drug inactive until it reaches the target site. Monoclonal antibodies (mAbs), which have shown high binding specificity for tumor-specific antigens, could be used as targeting agents. Paclitaxel has brought significant impact on the current cancer chemotherapy, but seriously suffers from the lack of tumor specificity. A series of paclitaxel-monoclonal antibody conjugates via C-2' ester linkage were reported. Taking into account the fact that the cytotoxicity of paclitaxel is not good enough and thus not applicable to this target delivery prodrug approach, new taxoids bearing methyldisulfanyl(alkanoyl) groups were designed, synthesized, and their activities evaluated. A highly cytotoxic C-10 methyldisulfanyl-propanoyl taxoid, was conjugated to monoclonal antibodies recognizing the epidermal growth factor receptor (EGFR). These conjugates were shown to possess remarkable target-specific antitumor activity in vivo against EGFR-expressing A431 tumor xenografts in SCID mice, resulting in complete inhibition of tumor growth in all the treated mice without any noticeable toxicity to the animals.

Recent advances in the medicinal chemistry of taxoids with novel beta-amino acid side chains.

Beta-Amino acids have been recognized as an important class of compounds in the design and synthesis of potential pharmaceutical drugs and also for the study of enzymatic reaction mechanisms. Among the beta-amino acid family, isoserines (alpha-hydroxy-beta-amino acids) are probably the most important members because many of them are potent enzyme inhibitors and they also serve as essential building blocks for biologically and medicinally important molecules such as Taxol. Taxol (paclitaxel) and Taxotère (docetaxel) are currently considered to be the most important drugs in cancer chemotherapy. This review describes recent advances in the chemistry of isoserines and taxoid anticancer agents at the biomedical interface including (i) the development of highly efficient method for the synthesis of isoserine side chains of taxoids and (ii) the synthesis and structure-activity relationship (SAR) study of taxoids featuring discovery and development of the "second generation" taxoid anticancer agents that possess exceptional activities against drug-resistant cancer cells.

Synthesis and structure-activity relationships of nonaromatic taxoids: effects of alkyl and alkenyl ester groups on cytotoxicity.

Several new nonaromatic taxoids are synthesized by means of the beta-lactam synthon method. These include taxoids modified with 3-methylbut-2-enoate, 3-methylbutanoate, and cyclohexanecarboxylate groups in place of the benzoate at the C-2 position. In addition, taxoids with 2-methylprop-1-enyl, 2-methylpropyl, (E)-prop-1-enyl, and cyclohexyl groups at the C-3' position are also prepared in combination with the modifications at C-2. The alkyl and alkenyl ester groups at C-2 displayed pronounced effects on the in vitro cytotoxicity. Two of the fully aliphatic taxoids possess similar or stronger activity than paclitaxel and docetaxel. It is clear that the 2-benzoate does not play a unique role, and replacement with the appropriate alkyl and alkenyl groups provides taxoids with equivalent or superior activity.

Synthesis and structure-activity relationships of new antitumor taxoids. Effects of cyclohexyl substitution at the C-3' and/or C-2 of taxotere (docetaxel).

Synthesis and cytotoxicity of the new analogs (11-13) of docetaxel possessing cyclohexyl groups instead of phenyl groups at the C-3' and/or C-2 benzoate positions are described. The C-2 cyclohexanecarboxylate analog of paclitaxel (15) is also synthesized for comparison. The potency of these new taxoids were examined for their inhibitory activity for microtubule disassembly and also for their cytotoxicity against murine P388 leukemia cell line as well as doxorubicin-resistant P388 leukemia cell line (P388/Dox). It is found that 3'-dephenyl-3'-cyclohexyldocetaxel (11) (0.72T) and 2-(hexahydro)docetaxel (12) (0.85T) possess strong inhibitory activity for microtubule disassembly equivalent to docetaxel (0.7T), which is more potent than paclitaxel (1.0T). The results clearly indicate that phenyl or an aromatic group at C-3' or C-2 is not a requisite for strong binding to the microtubules. This finding has opened an avenue for development of new nonaromatic analogs of docetaxel and paclitaxel. 3'-Dephenyl-3'-cyclohexyl-2-(hexahydro)docetaxel (13) (2T) turns out to be a substantially weaker inhibitor. The cytotoxicities of 11-13 against P388 are, however, in the same range that is 8-12 times weaker than docetaxel and 4-6 times weaker than paclitaxel, i.e., 13 shows equivalent cytotoxicity to that of 11 or 12 in spite of much lower microtubule disassembly inhibitory activity. The cytotoxicities of these new taxoids against the P388/Dox cell line are only 2-2.5 times lower than that of docetaxel. The potency of 2-(hexahydro)paclitaxel (15) for these assays is much lower than the docetaxel counterpart 12. The significant loss of activity in vivo against B16 melanoma is observed for 11-13, i.e., 11 is only marginal (T/C = 38% at 20 mg/kg/day), and 12 and 13 are inactive (T/C = 76% and 79%, respectively). This could be ascribed to faster metabolism, faster excretion or other bioavailability problems.

Syntheses and structure-activity relationships of the second-generation antitumor taxoids: exceptional activity against drug-resistant cancer cells.

A series of new 3'-(2-methyl-1-propenyl) and 3'-(2-methylpropyl) taxoids with modifications at C-10 was synthesized by means of the beta-lactam synthon method using 10-modified 7-(triethylsilyl)-10-deacetylbaccatin III derivatives. The new taxoids thus synthesized show excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines. All but one of these new taxoids possess better activity than paclitaxel and docetaxel in the same assay, i.e., the IC50 values of almost all the taxoids are in the subnanomolar level. It is found that a variety of modifications at C-10 is tolerated for the activity against normal cancer cell lines, but the activity against a drug-resistant human breast cancer cell line expressing MDR phenotype (MCF7-R) is highly dependent on the structure of the C-10 modifier. A number of the new taxoids exhibit remarkable activity (IC50 = 2.1-9.1 nM) against MCF7-R. Among these, three new taxoids, SB-T-1213 (4a), SB-T-1214 (4b), and SB-T-1102 (5a), are found to be exceptionally potent, possessing 2 orders of magnitude better activity than paclitaxel and docetaxel. The observed exceptional activity of these taxoids may well be ascribed to an effective inhibition of P-glycoprotein binding by the modified C-10 moieties. The new taxoid SB-T-1213 (4a) shows an excellent activity (T/C = 0% at 12.4 and 7.7 mg/kg/dose, log10 cell kill = 2.3 and 2.0, respectively) against B16 melanoma in B6D2F1 mice via intravenous administration.

Syntheses and structure-activity relationships of taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III.

A series of new taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III was synthesized by means of the beta-lactam synthon method. Most of the new taxoids thus synthesized possess excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines, and several of these taxoids show subnanomolar IC50 values which are severalfold to 1 order of magnitude better than those of paclitaxel and docetaxel. Modifications at the 3'- and 3'-N-positions exert marked effects on the activity. For the substituents at C-3', the cytotoxicity decreases in the order 2-furyl approximately 2-methyl-1-propenyl > or = 2-methylpropyl > (E)-1-propenyl > or = n-propyl > phenyl > > 2,2-dimethylpropyl. For the 3'-N substituents, the activity decreases in the order t-BuOCO > Ph > n-hexanoyl. A significant increase in the cytotoxicity against the doxorubicin-resistant human breast cancer cell line MCF7-R that expresses the multidrug resistance (MDR) phenotype is observed by the proper modification of the substituent at C-10. The observed remarkable effects of the substituents at C-10 on the activity against MCF7-R can be ascribed to the effective inhibition of the binding of these new taxoids to P-glycoprotein that is responsible for MDR.

GPIIb/IIIa integrin antagonists with the new conformational restriction unit, trisubstituted beta-amino acid derivatives, and a substituted benzamidine structure.

Ethyl N-[3-(2-fluoro-4-(thiazolidin-3-yl(imino)methyl)benzoyl)amino-2, 2-dimethylpentanoyl]piperidine-4-acetate 40 (NSL-96184) is a highly potent and orally active fibrinogen receptor antagonist, which is characterized by the presence of the trisubstituted beta-amino acid residue, 3-ethyl-2,2-dimethyl-beta-alanine. This compound was developed on the basis of the SAR study of N-[3-(N-4-amidinobenzoyl)amino-2, 2-dimethyl-3-phenylpropionyl]piperidine-4-acetic acid 1(NSL-95301) with the derivatization focused on the central trisubstituted beta-amino acid unit as well as the basic amidinobenzoyl unit, and the esterification of the carboxyl group for prodrug composition. Compound 1, which was reported in our previous study, was discovered by the application of combinatorial chemistry. The molecular modeling study suggests that the trisubstituted beta-amino acid unit is responsible for fixing the molecule to its active conformation. Compound 40 showed an excellent profile in the in vitro and in vivo studies for its human platelet aggregation inhibitory activity and oral availability in guinea pigs. This oral availability largely depends on the modification of the amidino group with a cyclic secondary amine, i.e., thiazolidine in 40. In in vivo studies, the onset of the antiplatelet action of 40 is very fast after oral administration, whereas its duration of action is relatively short. These results suggest that 40 has an excellent therapeutic potential, especially for antithrombotic treatment in the acute phase. 3-Substituted-2,2-dimethyl-beta-amino acid residues would serve as new and useful linear templates to restrict the conformational flexibility of peptidomimetics.

Desymmetrization of 4-dimethylsiloxy-1,6-heptadiynes through sequential double silylformylation.

[reaction in text] Desymmetrization of dimethylsilyloxyalkadiynes (1) by Rh-catalyzed intramolecular silylformylation affords 5-exo-(formylmethylene)oxasilacyclopentanes 2 in high yields. Novel sequential double silylformylation of 1a also provides desymmetrization, giving 3-(3-silyl-2-formylprop-2-enyl)-5-exo-(formylmethylene)oxasilacyclopentanes 4 in excellent yields. Reduction of 2a and 4 with NaBH(4) gives the corresponding 5-exo-(hydroxymethylmethylene)oxasilacyclopentanes 3a and 5, respectively.

Novel DMAP-catalyzed skeletal rearrangement of 5-exo-(2-hydroxy-ethylene)oxasilacyclopentanes.

[reaction: see text] 5-exo-(Hydroxyethylene)-2-oxa-1-silacyclopentanes are found to undergo a novel DMAP-catalyzed skeletal rearrangement through silicon-oxygen exchange during acetylation to yield the corresponding 5-(2-acetoxyalkyl)-2-oxa-1-silacyclopent-4-enes exclusively. The mechanism for this unprecedented rearrangement is proposed.

Synthesis and evaluation of 6-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine as a PET tracer for nicotinic acetylcholine receptors.

Both ABT-594 ((R)-2-chloro-5-(2-azetidinylmethoxy)pyridine) and A-85380 (3-[2(S)-2-azetidinylmethoxy]pyridine), novel nicotinic agonists that possess potent non-opioid analgesic properties, have high affinity for neuronal nicotinic acetylcholine receptors (nAChR) but do not elicit the pronounced toxicity of epibatidine. 6-[(18)F]Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-[(18)F]fluoro-A-85380), a F-18 labeled analogue of these two compounds, is therefore a promising radioligand for positron emission tomography (PET) studies in humans. The use of trimethylammonium as a leaving group in nucleophilic aromatic substitution reactions has proven to be a versatile and efficient strategy, and offers several advantages over other leaving groups. Here, we report the synthetic strategy for the preparation of a precursor, as a trimethylammonium iodide salt, and its use in the radiosynthesis to 6-[(18)F]fluoro-A-85380. Preliminary compartative PET studies of 6-[(18)F]fluoro-A-85380 and 2-[(18)F]fluoro-A-85380 were carried out in baboon to examine their suitability as tracers for studying nAChR system.

Cytotoxic effects toward human hematopoietic progenitor cells and tumor cell lines of paclitaxel, docetaxel, and newly developed analogues IDN5109, IDN5111, and IDN5127.

The growth inhibitory effect of paclitaxel, docetaxel, and newly developed taxanes IDN5109, IDN5111, and IDN5127 was assessed on peripheral blood (PB) CD34+ maintained in liquid culture and on three human cancer cell lines (MDA-MB231, MCF-7 ADRr, CEM VBLr). Concomitantly, DNA analysis was also performed. For unfractionated peripheral blood progenitor cells (PBPC) toxicity was also assessed by clonogenic assay. The cytotoxic effects induced by taxanes toward PBPC as measured by clonogenic assay were correlated with those found for multidrug resistance (MDR)-positive cell lines (IDN5109 > IDN5111 > IDN5127 > docetaxel > paclitaxel). We established a therapeutic index (TI) between the antitumor activity in MDR-positive cells and the toxicity toward PBPC. Paclitaxel and IDN5109, as determined by TI, showed the best value in MDR-negative and MDR-positive cells, respectively. The ranking of the cytotoxic effects observed in PB CD34+ was not correlated with that obtained in clonogenic assay and in cancer cells (IDN5127 > IDN5109 > docetaxel > IDN5111). Remarkably, in DNA analysis docetaxel induced the maximal cell cycle blocking activity. Newly developed taxanes IDN5109 and IDN5111 are endowed of a profile of anticancer activity in MDR-bearing cells and toxicity toward hematopoietic progenitors better than that of docetaxel. However, mechanism(s) underlying toxicity toward hematopoietic progenitors could be, at least in part, different from that of docetaxel and likely dependent on the interaction with P-glycoprotein function in PB CD34+ cells.

Antitumor efficacy of taxane liposomes on a human ovarian tumor xenograft in nude athymic mice.

Taxanes such as paclitaxel (Taxol) and docetaxel (Taxotere) are promising agents for use against ovarian cancer and other malignancies. Recently, SB-T-1011, a semisynthetic taxane, has been prepared from 14-hydroxy-10-deacetylbaccatin III. SB-T-1011 shows similar or greater in vitro cytostatic activity than paclitaxel, depending on the tumor cell line. The administration of taxanes is problematic due to their low solubility in most pharmaceutically acceptable solvents; formulations used clinically contain Cremophor/ethanol (diluent 12) or polysorbate 80/ethanol, excipients which may cause serious adverse effects. To eliminate these vehicles, we have prepared paclitaxel liposome formulations. The objective of the present work was to evaluate the antitumor activity of paclitaxel and two semisynthetic analogs in Cremophor-based and liposomal formulations. Antitumor activity was evaluated against A121a, a taxane-sensitive human ovarian tumor, growing as subcutaneous xenografts in athymic nude mice. Free and liposomal formulations of each taxane showed similar antitumor effect. The antitumor activity of paclitaxel and SB-T-1011 was similar, and docetaxel was more potent than either paclitaxel or SB-T-1011. Overall, taxane liposomes were better tolerated and more easily administered iv than taxane formulated in Cremophor/ethanol.

Syntheses of Norstatine, Its Analogs, and Dipeptide Isosteres by Means of ß-Lactam Synthon Method.

Nonprotein amino acids are the amino acids that are not found in protein-main chains and mostly originate in plants, microorganisms, and marine products. Certain nonprotein amino acids exhibit biological activities by themselves, and many of them are important constituents of biologically active compounds of medicinal interest. For this reason, in addition to the naturally occurring nonprotein amino acids, synthetic nonprotein amino acids have been studied extensively, especially in connection with the design and synthesis of various enzyme inhibitors. Indeed, statine, norstatine, and their analogs, as well as a variety of dipeptide isosteres, have been developed and incorporated in various inhibitors of enzymes such as renin and HIV-1 protease with great success (1). These amino acid residues and their isosteres provide effective transition-state mimics of the substrates for peptidases that bind to these enzymes tightly and inhibit their actions. Although a number of methods has been reported for the synthesis of statine and its analogs (2-7), to date, only a few synthetic methods are available for norstatine and its analogs (8-12). The ß-lactam synthon method developed by these laboratories (13-17) can be effectively applied to the asymmetric synthesis of norstatine and its analogs, as well as various dipeptide isosteres. In this chapter, the preparation of 3-siloxy-ß-lactams will be described first, followed by those of norstatine and its analogs, as well as dihydroxyethylene, hydroxyethylamine and other dipeptide isosteres.