114655-02-6

Purpose. Develop a Cremophor and solvent free formulation of paclitaxel using amphiphilic block co-polymer micelles of poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) and characterize their release, solubility, cytotoxicity, tolerability, and dis

The anticancer drug paclitaxel (Taxol) exhibits paradoxical and poorly understood effects against slow-growing tumors. To investigate its biological activity, fluorophores such as Oregon Green have been linked to this drug. However, this modification incr

Here we describe the first example of 2 nm gold nanoparticles (Au NPs) covalently functionalized with a chemotherapeutic drug, paclitaxel. The synthetic strategy involves the attachment of a flexible hexaethylene glycol linker at the C-7 position of pacli

Folate receptor (FR) has proven to be a valuable target for chemotherapy using folic acid (FA) conjugates. However, FA-conjugated chemotherapeutics still have low therapeutic efficacy accompanied with side effects, resulting from complications such as sho

A series of ferrocenyl analogues and derivatives of paclitaxel and docetaxel were synthesised and assayed for their antiproliferative/cytotoxic effects, impact on the cell cycle distribution and ability to induce tubulin polymerisation. The replacement of the 3′-N-benzoyl group of paclitaxel with a ferrocenoyl moiety, in particular, led to formation of an analogue that was at least one order of magnitude more potent in terms of antiproliferative activity than the parent compound (IC50values of 0.11 versus 1.11 μm, respectively), but still preserved the classical taxane mode of action, that is, microtubule stabilisation leading to mitotic arrest. Molecular docking studies revealed an unexpected binding pocket in the tubulin structure for the ferrocenoyl group introduced in the paclitaxel backbone.

Structure-efficacy effect of small molecular drug attracts wide attentions, but it has always been ignored in nanomedicine research. To reveal the efficacy modulation of nanomedicine, we developed a new type of paclitaxel (PTX)-conjugated gold nanoparticl

Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apopto

In this report, disulfide-crosslinked paclitaxel (PTX) prodrug micelles were developed through covalently conjugating PTX onto water soluble poly(ethylene glycol)-dihydrolipoic acid (MeO-PEG2k-DHLA) via a disulfide linkage and studied their perspectives for chemotherapic antitumor capacity. The polymer-PTX prodrug (MeO-PEG2k-SS-PTX), structurally determined by 1H NMR, possessed high PTX content up to 26 wt% and exhibited sharp reduction-responsive behavior. MeO-PEG2k-SS-PTX micelles were then subjected to crosslinking by oxidization of thiol (-SH) groups in the core of micellar particles after self-assembly of the amphimictic prodrug. The resultant crosslinked micelles were stable with spherical morphology having the uniform size of 87.67 nm in phosphate buffer (PBS, pH 7.4), as confirmed by transmission electron microscope (TEM) and dynamic light scattering (DLS). The cross-linked micelles based on the redox-sensitive MeO-PEG2k-SS-PTX prodrug exhibited an obvious glutathione (GSH)-dependant manner of fast PTX release with appropriate 65.6% in 12 h and 92.6% in 72 h after incubation in PBS medium containing 10 mM GSH. MTT assay together with apoptosis analysis showed that cross-linked MeO-PEG2k-SS-PTX micelles worked the higher antitumor activity against MCF-7, A549, BEL-7402 and 4T1 cells, using free PTX as a positive control. More importantly, such micelles were found to hold a longer circulation time in bloodstream and be able to passively targeting accumulate in tumor sites of 4T1-transplanted BALB/c mice model.

The invention provides a taxol-DHA-dextran coupling polymer, a synthetic method thereof and an application of the polymer, and belongs to the technical field of biological medicines. According to thepolymer, polysaccharides serve as polymer drug-loaded frameworks, so that an anti-tumor drug-polysaccharide passive targeted coupling polymer is prepared, taxol can be passively targeted into a tumortissue by the aid of an EPR effect, and an anti-tumor function is played. Water solubility and biocompatibility of taxol medicines can be increased, accumulation of anti-tumor medicines in the tumor tissue can be increased under the passive targeted action, general side effect and nervous side effect of the taxol medicines are reduced, and the polymer has good practical application values.

Prostate cancer (PC) is the second most commonly occurring cancer in men. Conventional chemotherapy has wide variety of disadvantages such as high systemic toxicity and low selectivity. Targeted drug delivery is a promising approach to decrease side effec

A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and βIII-tubulin overexpressed drug-resistant cancer cell lines were eval

The invention relates to a water-soluble antitumor compound represented by the formula (I), and further relates to a preparation method of the compound and an application of the compound in preparation of antitumor drugs. Stable prodrug with a good water

The invention provides taxanes with a structure represented by the formula I and a pharmaceutical composition thereof, and a use thereof; in particular, the use is a use for preparing anti-tumor drugs, wherein tumors include lung cancer, breast cancer, ga

Because of its overexpression in a range of solid tumors, the EphA2 receptor is a validated target for cancer therapeutics. We recently described a new targeted delivery system based on specific EphA2-targeting peptides conjugated with the chemotherapeutic agent paclitaxel. Here, we investigate the chemical determinants responsible for the stability and degradation of these agents in plasma. Introducing modifications in both the peptide and the linker between the peptide and paclitaxel resulted in drug conjugates that are both long-lived in rat plasma and that markedly decrease tumor size in a prostate cancer xenograft model compared with paclitaxel alone treatment. These studies identify critical rate-limiting degradation sites on the peptide-drug conjugates, enabling the design of agents with increased stability and efficacy. These results provide support for our central hypothesis that peptide-drug conjugates targeting EphA2 represent an innovative and potentially effective strategy to selectively deliver cytotoxic drugs to cancer cells. Ready, aim, fire! We investigated the chemical determinants responsible for the stability and degradation in plasma of an EphA2-based targeted delivery system that is constituted by receptor-targeting peptides conjugated with paclitaxel. We demonstrate that our agents are both long-lived in plasma and markedly decrease tumor size in a prostate cancer xenograft model.

Small-molecule ligands that control the spatial location of proteins in living cells would be valuable tools for regulating biological systems. However, the creation of such molecules remains almost unexplored because of the lack of a design methodology. Here we introduce a conceptually new type of synthetic ligands, self-localizing ligands (SLLs), which spontaneously localize to specific subcellular regions in mammalian cells. We show that SLLs bind their target proteins and relocate (tether) them rapidly from the cytoplasm to their targeting sites, thus serving as synthetic protein translocators. SLL-induced protein translocation enables us to manipulate diverse synthetic/endogenous signaling pathways. The method is also applicable to reversible protein translocation and allows control of multiple proteins at different times and locations in the same cell. These results demonstrate the usefulness of SLLs in the spatial (and temporal) control of intracellular protein distribution and biological processes, opening a new direction in the design of small-molecule tools or drugs for cell regulation.

The efficacy of anticancer drugs is often limited by their systemic toxicities and adverse side effects. We report that the EphA2 receptor is overexpressed preferentially in several human cancer cell lines compared to normal tissues and that an EphA2 targeting peptide (YSAYPDSVPMMS) can be effective in delivering anticancer agents to such tumors. Hence, we report on the synthesis and characterizations of a novel EphA2-targeting agent conjugated with the chemotherapeutic drug paclitaxel. We found that the peptide-drug conjugate is dramatically more effective than paclitaxel alone at inhibiting tumor growth in a prostate cancer xenograft model, delivering significantly higher levels of drug to the tumor site. We believe these studies open the way to the development of a new class of therapeutic compounds that exploit the EphA2 receptor for drug delivery to cancer cells.

We previously reported a novel drug delivery system, drug-linker-Phe-Phe- Arg-methylketone (FFR-mk)-factor VIIa (fVIIa). The method utilizes tissue factor (TF), which is aberrantly and abundantly expressed on many cancer cells. The advantage of this delivery system is its ability to furnish a potent anticancer drug specifically to the tumor vasculature and cancer cells. In this paper, we describe the synthesis of paclitaxel (PTX)-Phe-Phe-Arg-chloromethyl ketone (FFR-ck), followed by coupling with fVIIa to form PTX-FFR-mk-fVIIa. FFRck was separately linked to the OH groups at the C2′ or C7 positions of PTX (C2′- or C7-PTX-FFRck), the C2′ analogue exhibiting better activity against human head and neck squamous KB 3-1 cells. The activity order against PTX-sensitive KB 3-1 cells is C2′-PTX-FFRmk-fVIIa > PTX > C2′-PTX-FFRck. The C2′ complex shows an IC50 of 12 nM against the PTX-sensitive cell line and 130 nM against PTX-resistant cells.

Three fluorescent probes 3a, 3b, and 4 have been synthesized through conjugation of fluorescein and difluorescein groups to the 7-OH of C-2 modified paclitaxel and cephalomannine derivatives with very high affinity to microtubules. All these probes exhibi

Conjugates of a cargo molecule with a transporter molecule are disclosed, where the cargo molecule and the transporter molecule are linked covalently by a releasable linker. The cargo of the conjugate can be a biologically active agent or a reporter molec

The present application relates to new taxane analogs, pharmaceutical compositions comprising such analogs and methods of treating cancer comprising such compositions. The compounds according to the present application have the general formula: wherein R

(Chemical Equation Presented) A method has been developed for the methylation of the C3′ amide of taxol C and paclitaxel. Taxol C and paclitaxel were sequentially silylated at the 2′, 7, and 1-hydroxyl groups with tert-butyldimethylsilyl chloride, triethy

The present invention relates to a novel chemical compound of formula S-(I) for use in the treatment of cancer, to compositions containing said compound, methods of manufacture and combinations with other therapeutic agents.

Provided herein are compounds and methods for the treatment of brain cancer in a mammal, wherein the method comprises the administration to the mammal a compound that stabilizes tubulin dimers or microtubles at G2-M interface during mitosis but is not a s

Sixteen different taxoid conjugates were prepared by linking various anticancer compounds, including camptothecin (CPT), epipodophyllotoxin (EP), colchicine (COL), and glycyrrhetinic acid (GA), at the 2′- or 7-position on paclitaxel (TXL, 1) through an ester, imine, amine, or amide bond. Newly synthesized conjugates were evaluated for cytotoxic activity against replication of several human tumor cell lines. Among them, TXL-CPT conjugates, 8-10, were more potent than TXL itself against the human prostate carcinoma cell line PC-3 (ED50 = 14.8, 3.1, 19.4 nM compared with 55.5 nM), and conjugate 10 was also 8-fold more active than TXL against the LN-CAP prostate cancer cell line. These compounds also possessed anti-angiogenesis ability as well as lower inhibitory effects against a normal cell line (MRC-5). Thus, conjugates 8-10 are possible antitumor drug candidates, particularly for prostate cancer.

7-Deoxypaclitaxel, 10-deacetoxypaclitaxel and 10-deacetoxy-7- deoxypaclitaxel were prepared and evaluated for their ability to promote assembly of tubulin into microtubules, their cytotoxicity against NCI/ADR-RES cells and for their interactions with P-gl

Efficient syntheses of two taxol analogs bearing the linear polyamine spermine at 7- and 10-positions of paclitaxel and 10-deacetyl-paclitaxel have been developed. These polyamine-taxol-conjugates were isolated as water soluble difluoride salts. The aim o

The present invention relates to new taxane analogs useful for the treatment of cancer as well as methods for producing the same. The chemical compounds according to the present invention have the general Formula (I) wherein R1 and R2 are each selected fr

The female steroid hormone 3,17β-estradiol (2) was selected as an agent to target taxol (1) to estrogen receptor (ER) positive breast cancer cells. Estradiol-taxol conjugates (ETC) were synthesized through linkages from the 11- or 16-position of estradiol

A series of paclitaxel analogues possessing a macrocyclic structure between the 7 and 10 positions has been prepared. These compounds possess in vitro activity against a paclitaxel resistant cell line and have in vivo activity comparable to paclitaxel.

A novel and efficient two-step, automated solution phase synthesis of a 26-membered combinatorial chemistry library of paclitaxel C7 esters was accomplished using the HP 7686 Solution Phase Synthesizer. Results of combinatorial synthesis, purification, analysis, and biological evaluation are described.

The anticancer drug paclitaxel (Taxol) has been converted to a large number of 2-debenzoyl-2-aroyl derivatives by three different methods. The bioactivities of the resulting analogues were determined in both tubulin polymerization and cytotoxicity assays, and several analogues with enhanced activity as compared with paclitaxel were discovered. Correlation of cytotoxicity in three cell lines with tubulin polymerization activity showed reasonable agreement. Among the cell lines examined, the closest correlation with antitubulin activity was observed with a human ovarian carcinoma cell line.

Two new taxol analogs 6 and 10 have been prepared from baccatin III (1) and taxol (7a), respectively. Like taxol, both compounds were found to promote microtubule formation and stabilization, although they were less active than taxol. Both 6 and 10 exhibi

The synthesis and biological evaluation of several 7-O-acylpaclitaxel analogues as potential photoaffinity, electrophilic, and fluorescent probes are described.

The synthesis and biological evaluation of the two known phenolic metabolites of paclitaxel are described. The C3'-phenolic metabolite 2 of paclitaxel was prepared from 7-(triethylsilyl)-baccatin III (8) and enantioenriched N-benzoyl-2-azetidinone 7. The C2-phenolic metabolite 3 was synthesized from paclitaxel (1a) via selective C2 debenzoylation and reacylation.

A method has been developed for the syntheses of hitherto unreported C-9 and C-10 modified taxanes.These analogs demonstrated excellent to good cytotoxicity against B 16 melanoma cells.

Both 7-deoxy-7α-azidopaclitaxel (6) and 7-deoxy-Δ6,7-paclitaxel (4) can be prepared from paclitaxel-7-O-triflate (2b).Oxidation of 7-deoxy-Δ6,7-paclitaxel with dioxirane yields the epoxide 7, while oxidation with osmium tetroxide yie

4-Deacetylpaclitaxel, prepared from baccatin III via two synthetic approaches and from paclitaxel via one synthetic approach, has minimal effects on tubulin polymerization and is not cytotoxic to human CA46 Burkitt lymphoma cells.

Hydrolytic procedures for selective 2-debenzoylation and 2,4-dideacylation of 2'-O-tert-butyldimethylsilyl-7-O-(triethylsilyl)taxol are reported. The first synthesis and biological evaluation of a 4-substituted analogue, 4-deacetyl-4-isobutanoyltaxol, is