RESUMO
The carbon skeleton of any organic molecule serves as the foundation for its three-dimensional structure, playing a pivotal role in determining its physical and biological properties1. As such, taxane diterpenes are one of the most well-known natural product families, primarily owing to the success of their most prominent compound, paclitaxel, an effective anticancer therapeutic for more than 25 years2-6. In contrast to classical taxanes, the bioactivity of cyclotaxanes (also referred to as complex taxanes) remains significantly underexplored. The carbon skeletons of these two groups of taxanes differ significantly, and so would typically their own distinct synthetic approaches. Here we report a versatile synthetic strategy based on the interconversion of complex molecular frameworks, providing general access to the wider taxane diterpene family. A range of classical and cyclotaxane frameworks was prepared including, among others, the total syntheses of taxinine K (2), canataxapropellane (5) and dipropellane C from a single advanced intermediate. The synthetic approach deliberately eschews biomimicry, emphasizing instead the power of stereoelectronic control in orchestrating the interconversion of polycyclic frameworks.
Assuntos
Hidrocarbonetos Aromáticos com Pontes , Técnicas de Química Sintética , Diterpenos , Taxoides , Produtos Biológicos/síntese química , Produtos Biológicos/química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Carbono/química , Diterpenos/síntese química , Diterpenos/química , Estereoisomerismo , Taxoides/química , Taxoides/síntese química , Paclitaxel/químicaRESUMO
It has been shown that the incorporation of fluorine or organofluorine groups into pharmaceutical and agricultural drugs often induces desirable pharmacological properties through unique protein-drug interactions involving fluorine. We have reported separately remarkable effects of the 2,2-difluorovinyl (DFV) group at the C3' position, as well as those of the CF3O and CHF2O groups at the 3-position of the C2-benzoyl moiety of the 2nd- and 3rd-generation taxoids on their potency and pharmacological properties. Thus, it was very natural for us to investigate the combination of these two modifications in the 3rd-generation taxoids and to find out whether these two modifications are cooperative at the binding site in the ß-tubulin or not, as well as to see how these effects are reflected in the biological activities of the new 3rd-generation DFV-taxoids. Accordingly, we designed, synthesized and fully characterized 14 new 3rd-generation DFV-taxoids. These new DFV-taxoids exhibited remarkable cytotoxicity against human breast, lung, colon, pancreatic and prostate cancer cell lines. All of these new DFV-taxoids exhibited subnanomolar IC50 values against drug-sensitive cell lines, A549, HT29, Vcap and PC3, as well as CFPAC-1. All of the novel DFV-taxoids exhibited 2-4 orders of magnitude greater potency against extremely drug-resistant cancer cell lines, LCC6-MDR and DLD-1, as compared to paclitaxel, indicating that these new DFV-taxoids can overcome MDR caused by the overexpression of Pgp and other ABC cassette transporters. Dose-response (kill) curve analysis of the new DFV-taxoids in LCC6-MDR and DLD-1 cell lines revealed highly impressive profiles of several new DFV-taxoids. The cooperative effects of the combination of the 3'-DFV group and 3-CF3O/CHF2O-benzoyl moiety at the C2 position were investigated in detail by molecular docking analysis. We found that both the 3'-DFV moiety and the 3-CF3O/3-CHF2O group of the C2-benzoate moiety are nicely accommodated to the deep hydrophobic pocket of the paclitaxel/taxoid binding site in the ß-tubulin, enabling an enhanced binding mode through unique attractive interactions between fluorine/CF3O/CHF2O and the protein beyond those of paclitaxel and new-generation taxoids without bearing organofluorine groups, which are reflected in the remarkable potency of the new 3rd-generation DFV-taxoids.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Flúor/farmacologia , Taxoides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Flúor/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Taxoides/síntese química , Taxoides/química , Células Tumorais CultivadasRESUMO
Natural products with a high ratio of sp3-hybridized atoms and oxygen-substituted stereogenic centers represent privileged structures for the development of pharmaceuticals and chemical probes. The multiple oxygen functionalities of these natural products endow their potent and selective biological activities, although they significantly heighten the challenge of their chemical assemblies. We focused on developing efficient strategies for the total syntheses of this biologically and chemically important class of molecules. A convergent strategy is more advantageous than a linear strategy for designing a shorter synthetic route because a convergent strategy enables direct coupling of functionalized fragments whereas a linear strategy involves stepwise construction of a molecule from its terminus. Radical reactions are preferred over polar reactions for the coupling of heavily functionalized and sp3-rich fragments, as they allow for C(sp3)-C(sp3) coupling without damaging diverse polar functional groups. With these considerations in mind, we designed radical-based convergent strategies for assembling highly oxygenated natural products. Here we summarize the concise total syntheses of asimicin (1, antibiotic activity), 1-hydroxytaxinine (2, cytotoxicity), polyoxins (3, antifungal activity), and hikizimycin (4, anthelmintic activity) as representative examples. Retrosynthetic disconnection at the central part of these molecules produces highly substituted α-alkoxy radicals as synthons. In the synthetic direction, the α-alkoxy radicals were generated from the corresponding α-alkoxyacyl tellurides in a unified fashion, and then utilized for four distinct coupling reactions. Formation of the Et radical from Et3B and O2 homolytically cleaves the C-Te bond of α-alkoxyacyl telluride, and the facile expulsion of carbon monoxide from the acyl radical leads to the α-alkoxy radical. Dimerization of the stabilized α-alkoxy radical resulted in the core structure of 1 with 10 contiguous stereocenters. The coupling adduct was derivatized to 1 through the attachment of two different carbon chains (17 steps as the longest linear sequence). Alternatively, intermolecular addition reactions of the α-alkoxy radicals to electron-deficient CâC, CâN, and CâO bonds, followed by Et3B-mediated radical termination, led to the core structures of 2, 3, and 4, respectively. Intermolecular coupling between the α-alkoxy radical and the cyclohexenone derivative and intramolecular pinacol coupling gave rise to the 6/8/6-fused ring system of 2, which was transformed to 2 (26 steps). The two amino acid moieties of 3 were prepared by combining the α-alkoxy radical and the oxime and were then condensed to complete the synthesis of 3 (11 steps). Furthermore, a combination of α-alkoxyacyl telluride and Et3B/O2 realized a novel addition reaction of α-alkoxy radicals to aldehydes. This method was incorporated in the construction of the core 4-amino-5-deoxyundecose with 10 contiguous stereocenters, which was fabricated with two appendage structures to deliver 4. The four total syntheses described here demonstrate the versatility and robustness of intermolecular radical reactions. These syntheses will also provide new insights for retrosynthetic analyses in the field of organic chemistry and streamline synthetic routes to various bioactive natural products with multiple oxygen functionalities.
Assuntos
Produtos Biológicos/síntese química , Radicais Livres/química , Oxigênio/química , Aminoglicosídeos/química , Produtos Biológicos/química , Desenho de Fármacos , Furanos/síntese química , Furanos/química , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/química , Teoria Quântica , Estereoisomerismo , Taxoides/síntese química , Taxoides/químicaRESUMO
A series of C-7, C-9 and C-10 modified taxane analogues were synthesized and their in vitro anticancer activities against three human cancer cell lines: A-549 (human lung cancer cell line), MDA-MB-231 (human breast cancer cell line), A-549/T (human lung cancer resistant cell line) were studied. The novel 1-deoxybaccatin VI derivatives modified with carbonate group at C-9 and C-10 positions enable the behavior of these compounds to be evidently distinct from other similar compounds. The strong cytotoxicity in the three cell lines, especially in drug-resistant cell line, showed by the newly synthesized taxane analogues indicated them as potential lead compounds for anticancer drug design.
Assuntos
Antineoplásicos/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Taxoides/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade , Taxoides/síntese química , Taxoides/farmacologiaRESUMO
Canataxpropellane belongs to the medicinally important taxane diterpene family. The most prominent congener, Taxol, is one of the most commonly used anticancer agent in clinics today. Canataxpropellane exhibits a taxane skeleton with three additional transannular C-C bonds, resulting in a total of six contiguous quaternary carbons, of which four are located on a cyclobutane ring. Unfortunately, isolation of canataxpropellane from natural sources is inefficient. Here, we report a total synthesis of (-)-canataxpropellane in 26 steps and 0.5% overall yield from a known intermediate corresponding to 29 steps from commercial material. The core structure of the (-)-canataxpropellane (2) was assembled in two steps using a Diels-Alder/ortho-alkene-arene photocycloaddition sequence. Enantioselectivity was introduced by designing chiral siloxanes to serve as auxiliaries in the Diels-Alder reaction.
Assuntos
Antineoplásicos/síntese química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Diterpenos/síntese química , Taxoides/síntese químicaRESUMO
It has been shown that inclusion of CF3O and CHF2O groups to drug candidates often improve their pharmacological properties, especially metabolic stability, membrane permeability and PK profile. Moreover, the unique non-spherical structure of the OCHF2 group can provide interesting and beneficial characteristics. Accordingly, new 3rd-generation taxoids, bearing 3-OCF3 or 3-OCF2H (and 3-CH3 for comparison) at the C2 benzoate moiety, were synthesized and their potencies against drug-sensitive and drug-resistant cancer cell lines examined. In this study, our previous SAR studies on 3rd-generation taxoids were expanded to disclose that CH3, CF3O and CHF2O groups are well tolerated at this position and enhance potency, especially against MDR-cancer cell lines so that these taxoids can virtually overcome MDR. These new taxoids exhibit up to 7 times higher cytotoxicity (IC50) than paclitaxel against drug-sensitive cancer cell lines (MCF7 and LCC6-WT) and 2-3 orders of magnitude higher potency than paclitaxel against drug-resistant ovarian, breast and colon cancer cell lines with MDR-phenotype (NCI/ADR, LCC6-MDR and LDL-1), as well as pancreatic cancer cell line, CFPAC-1. Since it has been shown that a bulky group at this position reduces potency, it is noteworthy that rather bulky CF3O and CHF2O groups are well tolerated. Molecular modeling analysis indicated the favorable van der Waals interactions of CF3O and CHF2O groups in the binding site. It is also worthy of note that new taxoids, bearing a CHF2O group at the C2 benzoate position (1-06 series), exhibited the highest potencies against MDR-cancer cell lines and cancer stem cell (CSC)-enriched cancer cell lines. These new 3rd-generation taxoids are promising candidates for highly potent chemotherapeutic agents, as well as payloads for tumor-targeting drug conjugates such as antibody-drug conjugates (ADCs).
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Benzoatos/química , Desenho de Fármacos , Taxoides/química , Taxoides/farmacologia , Antineoplásicos Fitogênicos/síntese química , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Relação Estrutura-Atividade , Taxoides/síntese químicaRESUMO
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 ßIII-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via carbonate containing-linked macrocyclization display increased cytotoxicity on drug-resistant tumors overexpressing both ßIII and P-gp, among which compound 22b, bearing a 2-m-methoxybenzoyl group together with a five-atom linker, was identified as the most potent. Molecular modeling suggested the improved cytotoxicity of 22b results from enhanced favorable interactions with the T7 loop region of ßIII.
Assuntos
Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Taxoides/síntese química , Taxoides/farmacologia , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Morte Celular/efeitos dos fármacos , Docetaxel/síntese química , Docetaxel/química , Docetaxel/farmacologia , Células HeLa , Humanos , Compostos Macrocíclicos/química , Simulação de Acoplamento Molecular , Paclitaxel/síntese química , Paclitaxel/química , Paclitaxel/farmacologia , Homologia Estrutural de Proteína , Taxoides/química , Tubulina (Proteína)/químicaRESUMO
Renal cell carcinoma (RCC) has always been considered resistant to chemotherapy. IR-780 is a near-infrared fluorescent (NIRF) dye that can be efficiently taken up by RCC cells. Cabazitaxel is a cytotoxic drug that interferes with mitosis by acting on tubulin. We chemically fused IR-780 and cabazitaxel into a new drug, Caba-780, which is expected to increase the sensitivity of RCC to chemotherapy. Infrared spectrum, nuclear magnetic resonance spectra, high-resolution mass spectra, and IR spectra were used for detecting structural characterization of the new synthetic drug Caba-780. The RCC cells lines ACHN and 786-O, as well as the non-cancerous human embryonic kidney cell line HEK293, were used to assess the cytotoxicity and tumor-efficient uptake of Caba-780 in vitro. The xenograft tumor-bearing mice and C57 mice were used to estimate the tumor-efficient imaging of Caba-780 as well as the safety and efficacy of its anti-tumor effects in vivo. The new synthetic drug Caba-780 retains the NIRF properties of IR-780. In vitro, Caba-780 was efficiently absorbed by the RCC cell lines ACHN and 786-O, and had an inhibitory effect on their growth, clonogenicity migration, and invasion. At the same time, Caba-780 retained the anti-tumor effect of cabazitaxel, which can inhibit the growth of tumor cells and promote apoptosis by inhibiting mitosis. In vivo experiments showed that Caba-780 can be taken up and imaged in tumor tissue, whereby it inhibits tumor growth. The novel fused molecule Caba-780 has application prospects in the diagnosis and treatment of RCC and makes RCC chemotherapy possible.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Raios Infravermelhos , Neoplasias Renais/tratamento farmacológico , Taxoides/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Neoplasias Renais/patologia , Camundongos , Invasividade Neoplásica , Transportadores de Ânions Orgânicos/metabolismo , Frações Subcelulares/metabolismo , Taxoides/síntese química , Taxoides/química , Taxoides/farmacologia , Testes de Toxicidade AgudaRESUMO
Four C-13, C-14 side chain modified 9(R)-hydroxy-1-deoxy-taxane analogues 15, 16, 19 and 22 were semi-synthesized from 1-deoxybaccatin VI. The in vitro antitumor activity of these compounds was evaluated against A549 and A2780 cell lines. The preliminary SAR analysis showed that introduction of oxygen-containing group on C-14 could improve the cytotoxic activities.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Taxoides/síntese química , Taxoides/farmacologia , Células A549 , Hidrocarbonetos Aromáticos com Pontes/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Relação Estrutura-Atividade , Taxoides/químicaRESUMO
Taxoid 10ß-O-acetyl transferase (DBAT) is a key enzyme in the biosynthesis of the famous anticancer drug paclitaxel, which catalyses the formation of baccatin III from 10-deacetylbaccatin III (10-DAB). However, the activity essential residues of the enzyme are still unknown, and the acylation mechanism from its natural substrate 10-deacetylbaccatin III and acetyl CoA to baccatin III remains unclear. In this study, the homology modelling, molecular docking, site-directed mutagenesis, and kinetic parameter determination of the enzyme were carried out. The results showed that the enzyme mutant DBATH162A resulted in complete loss of enzymatic activity, suggesting that the residue histidine at 162 was essential to DBAT activity. Residues D166 and R363 which were located in the pocket of the enzyme by homology modelling and molecular docking were also important for DBAT activity through the site-directed mutations. Furthermore, four amino acid residues including S31 and D34 from motif SXXD, D372 and G376 from motif DFGWG also played important roles on acylation. This was the first report of the elucidation of the activity essential residues of DBAT, making it possible for the further structural-based re-design of the enzyme for efficient biotransformation of baccatin III and paclitaxel.
Assuntos
Acetilcoenzima A/química , Aldeído-Cetona Transferases/química , Alcaloides/síntese química , Simulação de Acoplamento Molecular , Proteínas de Plantas/química , Taxoides/síntese química , Taxus/enzimologia , Aldeído-Cetona Transferases/genética , Alcaloides/química , Substituição de Aminoácidos , Mutação de Sentido Incorreto , Paclitaxel/síntese química , Paclitaxel/química , Proteínas de Plantas/genética , Taxoides/química , Taxus/genéticaRESUMO
Next-generation taxoids, such as SB-T-1214, are highly potent cytotoxic agents that exhibit remarkable efficacy against drug-resistant tumors in vivo, including those that overexpress the P-glycoprotein (Pgp) efflux pump. As SB-T-1214 is not a substrate for Pgp-mediated efflux, it may exhibit a markedly different biodistribution and tumor-accumulation profile than paclitaxel or docetaxel, which are both Pgp substrates. To investigate the biodistribution and tumor-accumulation levels of SB-T-1214 using positron emission tomography (PET), a new synthetic route has been developed to allow the incorporation of 11C, a commonly employed positron-emitting radionucleide, via methyl iodide at the last step of chemical synthesis. This synthetic route features a highly stereoselective chiral ester enolate-imine cyclocondensation, regioselective hydrostannation of the resulting ß-lactam, and the Stille coupling of the novel vinylstannyl taxoid intermediate with methyl iodide. Conditions have been established to allow the rapid methylation and HPLC purification of the target compound in a time frame amenable to 11C-labeling for applications to PET studies.
Assuntos
Radioisótopos de Carbono/química , Taxoides/química , Taxoides/síntese química , Catálise , Técnicas de Química Sintética , Marcação por Isótopo , Cinética , Metilação , Paládio/química , Tomografia por Emissão de PósitronsRESUMO
Three novel nor-seco-taxoids 13, 15, 23 in which the A rings are cleaved but the B, C, and D rings are retained were prepared from 1-deoxybaccatin VI via its nor-dioxo derivative and their structures were confirmed by 1H NMR, 13C NMR and high resolution MS. Oxidative introduction of C-1 hydroxyl to 1-deoxybaccatin VI with oxidising agent KBrO3 and catalyst RuCl3 led to the dioxo derivative 6 and its structure is determined by X-ray crystallographic analysis. A-seco taxoids 13, 15, 23 with a C-13 ester linkage were tested for cytotoxic activity and all compounds showed no measurable cytotoxic activity against HCT-116 cell line. However, 1-deoxy-9a-dihydrotaxane analogue 4 semi-synthesised from 1-deoxybaccatin VI is 10-fold less cytotoxic than paclitaxel, indicating the indispensible nature of the A ring double bond for the bioactivity of paclitaxel.
Assuntos
Taxoides/síntese química , Taxoides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Células HCT116 , Humanos , Estrutura Molecular , Oxirredução , Paclitaxel/farmacologia , Análise Espectral , Taxoides/químicaRESUMO
Theranostics will play a significant role in the next-generation chemotherapy. Two novel tumor-targeting theranostic drug conjugates, bearing imaging arms, were designed and synthesized. These theranostic conjugates consist of biotin as the tumor-targeting moiety, a second generation taxoid, SB-T-1214, as a potent anticancer drug, and two different imaging arms for capturing 99mTc for SPECT (single photon emission computed tomography) and 64Cu for PET (positron emission tomography). To explore the best reaction conditions for capturing radionuclides and work out the chemistry directly applicable to "hot" nuclides, cold chemistry was investigated to capture 185Re(I) and 63Cu(II) species as surrogates for 99mTc and 64Cu, respectively.
Assuntos
Biotina/análogos & derivados , Desenho de Fármacos , Neoplasias/diagnóstico por imagem , Taxoides/síntese química , Nanomedicina Teranóstica , Triazinas/síntese química , Animais , Biotina/síntese química , Quelantes/síntese química , Química Click , Cobre/química , Tomografia por Emissão de Pósitrons , Rênio/química , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
In our efforts to improve the efficacy of taxane-based microtubule (MT) stabilizing agents against tumor drug resistance mediated by multiple mechanisms, two clinically relevant factors were focused: i.e., P-glycoprotein and ßIII-tubulin overexpression. Based on the structure of C-seco taxoid 1 m (IDN5390) which was believed to more selectively interact with ßIII-tubulin than paclitaxel, we prepared a series of C-seco taxoids bearing various 7,9-O-linkages and/or different substituents at C2 and C3' positions. Some of them exhibited much more potent binding affinity to MTs and cytotoxicity than their C-seco parent compounds in drug resistant cells with both mechanisms. SAR analysis indicated that C2 modifications significantly enhanced MT binding but brought ambiguous influence to cytotoxicity whereas 7,9-linkage and C3' modifications enhance cytotoxicity more efficiently than improve MT binding. These observations illustrate a better translation of molecular binding effect to cellular activity by C ring closure and C3' modification than C2 modification in C-seco taxoids.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Taxoides/farmacologia , Tubulina (Proteína)/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Microtúbulos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Taxoides/síntese química , Taxoides/química , Tubulina (Proteína)/metabolismoRESUMO
Structure-activity relationship studies show that the phenylisoserinyl moiety of paclitaxel (Taxol) is largely necessary for the effective anticancer activity. Several paclitaxel analogues with a variant isoserinyl side chain have improved pharmaceutical properties versus those of the parent drug. To produce the isoserinyl CoAs as intermediates needed for enzyme catalysis on a semibiosynthetic pathway to paclitaxel analogues, we repurposed the adenylation and thiolation domains (Phe-AT) of a nonribosomal peptide synthetase (TycA) so that they would function as a CoA ligase. Twenty-eight isoserine analogue racemates were synthesized by an established procedure based on the Staudinger [2+2] cycloaddition reaction. Phe-AT converted 16 substituted phenylisoserines, one ß-(heteroaryl)isoserine, and one ß-(cyclohexyl)isoserine to their corresponding isoserinyl CoAs. We imagine that these CoA thioesters can likely serve as linchpin biosynthetic acyl donors transferred by a 13-O-acyltransferase to a paclitaxel precursor baccatin III to make drug analogues with better efficacy. It was also interesting to find that an active site mutant [Phe-AT (W227S)] turned over 2-pyridylisoserine and the sterically demanding p-methoxyphenylisoserine substrates to their CoA thioesters, while Phe-AT did not. This mutant is promising for further development to make 3-fluoro-2-pyridylisoserinyl CoA, a biosynthetic precursor of the oral pharmaceutical tesetaxel used for gastric cancers.
Assuntos
Antineoplásicos Fitogênicos/biossíntese , Coenzima A/química , Escherichia coli/genética , Peptídeo Sintases/química , Proteínas de Plantas/química , Engenharia de Proteínas , Alcaloides/biossíntese , Alcaloides/síntese química , Antineoplásicos Fitogênicos/síntese química , Brevibacillus/química , Brevibacillus/enzimologia , Domínio Catalítico , Clonagem Molecular , Coenzima A/metabolismo , Escherichia coli/enzimologia , Expressão Gênica , Cinética , Modelos Moleculares , Paclitaxel/biossíntese , Paclitaxel/síntese química , Peptídeo Sintases/genética , Peptídeo Sintases/metabolismo , Proteínas de Plantas/metabolismo , Domínios Proteicos , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Taxoides/síntese química , Taxoides/metabolismo , Taxus/química , Taxus/enzimologiaRESUMO
In the realm of natural product chemistry, few isolates have risen to the level of fame justifiably accorded to Taxol (1) and its chemical siblings. This report describes the most concise route to date for accessing the highly oxidized members of this family. As representative members of taxanes containing five oxygen atoms, decinnamoyltaxinineâ E (2) and taxabaccatinâ III (3), have succumbed to enantioselective total synthesis for the first time in only 18 steps from a simple olefin starting material. The strategy holistically mimics nature's approach (two-phase synthesis) and features a carefully choreographed sequence of stereoselective oxidations and a remarkable redox-isomerization to set the key trans-diol present in 2 and 3. This work lays the critical groundwork necessary to access even higher oxidized taxanes such as 1 in a more practical fashion, thus empowering a medicinal chemistry campaign that is not wedded to semi-synthesis.
Assuntos
Taxoides/síntese química , Conformação Molecular , Oxirredução , Estereoisomerismo , Taxoides/químicaRESUMO
Tricyclic isotaxane and taxane derivatives have been synthesized by a very efficient cascade ring-closing dienyne metathesis (RCDEYM) reaction, which formed the A and B rings in one operation. When the alkyne is present at C13 (with no neighboring gem-dimethyl group), the RCEDYM reaction leads to 14,15-isotaxanes 16 a,b and 18 b with the gem-dimethyl group on the A ring. If the alkyne is at the C11 position (and thus flanked by a gem-dimethyl group), RCEDYM reaction only proceeds in the presence of a trisubstituted olefin at C13, which disfavors the competing diene ring-closing metathesis reaction, to give the tricyclic core of Taxol 44.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Taxoides/química , Taxoides/síntese química , Alcenos/química , Alcinos/química , Técnicas de Química Sintética , Ciclização , Cicloparafinas/síntese química , Isomerismo , Estrutura MolecularRESUMO
The synthesis and preliminary evaluation of derivatives of docetaxel with novel amino acid as a linker named as LK-193ËLK-196 was described. The C2'-modified compound LK-196 behaves as a prodrug; that is, docetaxel is generated upon exposure to human plasma. The compound was also found to have greatly improved water solubility. The pharmacodynamic results showed LK-196 had the self-evident inhibitory effect on tumor growth in vivo, which is a promising candidate for further biological evaluation.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Desenho de Fármacos , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Taxoides/química , Taxoides/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Taxoides/síntese química , Taxoides/farmacocinética , Água/químicaRESUMO
Nanostructured lipid carriers (NLC) have been considered as promising vehicles for oral delivery of taxanes, such as docetaxel (DTX). However, the low drug loading capability (â¼5%, w/w) has greatly limited their clinical application. In response to this challenge, a novel lipophilic oleate prodrug of DTX (DTX-OA) was synthesized and efficiently encapsulated in NLC using core-match technology, in which liquid lipid (OA) was used as core matrix to enhance compatibility with DTX-OA. DTX-OA-NLC showed uniform particle size of about 100nm with markedly high drug loading capability (â¼23% of DTX, w/w) compared with DTX-NLC (â¼5%, w/w). Besides, DTX-OA-NLC showed better colloidal stability and slower drug release property compared with DTX-NLC. The prepared NLC could be accumulated more easily in MDCK cells than drug solution, and clathrin-mediated endocytosis was the main endocytosis pathway. In situ single-pass intestinal perfusion (SPIP) and intestinal biodistribution studies demonstrated the improved membrane permeability and intestinal wall bioadhesion of NLCs. The bioavailability of DTX-OA-NLC showed 4.04-fold and 2.06-fold higher than DTX solution and DTX-NLC, respectively. These results suggest that the core-matched prodrug-NLC is a promising platform to facilitate the oral delivery of DTX.
Assuntos
Antineoplásicos/farmacocinética , Portadores de Fármacos , Nanoestruturas/química , Pró-Fármacos/farmacocinética , Taxoides/farmacocinética , Administração Oral , Animais , Antineoplásicos/síntese química , Disponibilidade Biológica , Transporte Biológico , Docetaxel , Cães , Composição de Medicamentos/métodos , Endocitose/fisiologia , Glicerídeos/química , Interações Hidrofóbicas e Hidrofílicas , Absorção Intestinal/fisiologia , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Células Madin Darby de Rim Canino , Ácidos Oleicos/química , Tamanho da Partícula , Pró-Fármacos/síntese química , Ratos , Ratos Sprague-Dawley , Taxoides/síntese química , Distribuição Tecidual , Vitamina E/químicaRESUMO
CONTEXT: Technology for development of biodegradable nanoparticles encapsulating combinations for enhanced efficacy. OBJECTIVE: To develop docetaxel (DTX) and curcumin (CRM) co-encapsulated biodegradable nanoparticles for parenteral administration with potential for prolonged release and decreased toxicity. MATERIALS AND METHODS: Modified emulsion solvent-evaporation technique was employed in the preparation of the nanoparticles optimized by the face centered-central composite design (FC-CCD). The uptake potential was studied in MCF-7 cells, while the toxicity was evaluated by in vitro hemolysis test. In vivo pharmacokinetic was evaluated in male Wistar rats. RESULTS AND DISCUSSION: Co-encapsulated nanoparticles were developed of 219 nm size, 0.154 PDI, -13.74 mV zeta potential and 67.02% entrapment efficiency. Efficient uptake was observed by the nanoparticles in MCF-7 cells with decreased toxicity in comparison with the commercial DTX intravenous injection, Taxotere®. The nanoparticles exhibited biphasic release with initial burst release followed by sustained release for 5 days. The nanoparticles displayed a 4.3-fold increase in AUC (391.10 ± 32.94 versus 89.77 ± 10.58 µg/ml min) in comparison to Taxotere® with a 6.2-fold increase in MRT (24.78 ± 2.36 versus 3.58 ± 0.21 h). CONCLUSION: The nanoparticles exhibited increased uptake, prolonged in vitro and in vivo release, with decreased toxicity thus exhibiting potential for enhanced efficacy.