Search

Farnesoid X receptor (FXR) ligands have been actively pursued to treat metabolic disorders, liver and bile diseases, among others. Starting from a widely occurring natural product, oleanolic acid (OA), we discovered potent and selective FXR modulator from the 12β-oxygenated OA alkyl esters, with the assistance of molecular modeling. The representative compound 7b modulated some FXR downstream genes involved in glucose and lipid metabolism in cells, and significantly improved hyperglycemia in KKay fat mice fed with high fat diet, through the reduction of mRNA expression of gluconeogenesis genes PEPCK and G6Pase. This study provides a new series of selective FXR modulator, as well as the in vitro and in vivo evidence for their potential to improve hyperglycemia in diabetic mice through FXR antagonism.

Our purpose was to measure the temporomandibular joint (TMJ) synovial fluid (SF) levels of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) before and after intra-articular injection of hyaluronic acid (HA) and to investigate the possible mechanism involved in the therapeutic value of HA. We analysed the synovial fluid of 30 patients with unilateral internal derangement (ID) or osteoarthritis (OA) of the TMJ (confirmed by magnetic resonance imaging and cone-beam computed tomography) and recorded clinical signs and symptoms including maximal mouth opening, subjective joint pain, and joint noise at the patient's each visit. All clinical signs significantly improved after injection of HA, and there was no significant difference between ID and OA groups. In synovial fluid parameters, the concentration of VEGF was significantly higher before treatment with HA than after treatment, but there was no significant difference in the concentration of FGF-2 between before and after treatment. The study findings suggest intra-articular injection of HA may reduce the synovitis and improve the internal state of the TMJ in a short period.

Although the farnesoid X receptor (FXR) has been regarded as a promising drug target for metabolic diseases as well as anti-inflammatory, antitumor and antiviral actions, the antagonism by FXR ligands are still underrepresented in current FXR targeted therapies. In this study, we discovered selective FXR antagonists through structure optimization from the polyoxygenated chalcone scaffold. The selective antagonist 6 p [2-methoxy-2'-hydroxy-4'-(4''-methoxy-4''-oxo-E-crotonyl) chalcone] is not only inhibitory toward non-small-cell lung cancer (NSCLC) cell proliferation in an FXR-dependent manner, but is also active in metastasis models. Taken together, this chalcone-based FXR antagonist has the potential for the targeted therapy of NSCLC in which FXR is highly expressed.

The abnormally accumulated amyloid-β (Aβ) and oxidative stress contribute to the initiation and progression of Alzheimer's disease (AD). β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for the production of Aβ. Furthermore, Aβ was reported to increase oxidative stress; then the overproduced oxidative stress continues to increase the expression and activity of BACE1. Consequently, inhibition of both BACE1 and oxidative stress is a better strategy for AD therapy compared with those one-target treatment methods. In the present study, our novel small molecule YS-5-23 was proved to possess both of the activities. Specifically, we found that YS-5-23 reduces BACE1's expression in both SH-SY5Y and Swedish mutated amyloid precursor protein (APP) overexpressed HEK293 cells, and it can also suppress BACE1's expression induced by H2O2. Moreover, YS-5-23 decreases H2O2-induced cytotoxicity including alleviating H2O2-induced apoptosis and loss of mitochondria membrane potential (MMP) because it attenuates the reactive oxygen species (ROS) level elevated by H2O2. Meanwhile, PI3K/Akt signaling pathway is involved in the anti-H2O2 and BACE1 inhibition effect of YS-5-23. Our findings indicate that YS-5-23 may develop as a drug candidate in the prevention and treatment of AD.

Paclitaxel (Taxol®) is a taxane and a first-line chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules is well described, the current lack of high-resolution structural information on a tubulin-taxane complex precludes a comprehensive description of the binding determinants that affect the drug’s mechanism of action. Here, we solved the crystal structure of the core baccatin III moiety of paclitaxel lacking the C13 side chain in complex with tubulin at 1.9 Å resolution. Based on this information, we engineered two tailor-made taxanes with modified C13 side chains, solved their crystal structures in complex with tubulin, and analyzed their effects along with those of paclitaxel, docetaxel, and baccatin III on the microtubule lattice by X-ray fiber diffraction. We then compared high-resolution structures of ligand-bound tubulin and microtubule complexes with apo forms and used molecular dynamics simulations to understand the consequences of taxane binding to tubulin as well as to simplified protofilament and microtubule-lattice models. Our combined approach sheds light on three mechanistic questions. Firstly, taxanes bind better to microtubules as compared to unassembled tubulin due to a dual structural mechanism: Tubulin assembly is linked to a conformational reorganization of the βM loop, which otherwise occludes ligand access to the taxane site, while the bulky C13 side chains preferentially recognize the microtubule-assembled over the unassembled conformational state of tubulin. Second, the occupancy of the taxane site by a ligand has no influence on the straightness of tubulin protofilaments. Finally, binding of the taxane core to the taxane site displaces the S9-S10 loop of β-tubulin resulting in microtubule expansion. Our results provide detailed new insights into the mechanism of microtubule-stabilization by taxanes.

Background After transcatheter closure of atrial septal defect (ASD), it is still unclear about the in-vivo process of device-endothelialization in humans, which determines the duration of antiplatelet therapy. Based on contrast-uptake within device, cardiac-CT might have the potential to assess device-endothelialization indirectly. Purpose The study was conducted to investigate the status of device-endothelialization with cardiac-CT after transcatheter closure of ASD. Methods After more than 6 months of transcatheter ASD closure, cardiac-CT was performed in 119 patients (48M/71F; age: 46.7±14.4 years). According to contrast-uptake within device, complete or incomplete device-endothelialization was determined. In the latter, it was further divided into partial-endothelialization (with filling-defect) and no-endothelialization (without filling-defect). Multivariate logistic regression was used to determine the risk factors of incomplete device-endothelialization. In addition, device-endothelialization was analyzed grossly and histopathologically in 7 patients. Results During the implantation-period of 2.57±2.59 years, incomplete device-endothelialization was identified in 43.7% of patients (partial-endothelialization in 36 patients and no-endothelialization in 16 patients). Complete device-endothelialization occurred in 14.3% of patients during 0.5–1 year and 73.8% after one year. After 6-month antiplatelet therapy, migraine restarted in 15 patients with incomplete device-endothelialization and 3 patients with complete device-endothelialization. After one-year antiplatelet therapy, migraine was still detected in 4 of 15 patients with incomplete device-endothelialization. There was a significant association between high in-vivo device-thickness and incomplete device-endothelialization (P Conclusions Cardiac-CT had the potential to evaluate the status of device-endothelialization after transcatheter closure of ASD and there was a good clinico-pathological correlation. Incomplete device-endothelialization was common postoperatively in humans and was associated with device-oversizing. Further research is required to determine the appropriate duration of antiplatelet therapy after device implantation. Figure 1 Funding Acknowledgement Type of funding source: Other. Main funding source(s): National Natural Science Foundation of China

BACE1 inhibitory conjugates derived from two natural products, luteolin (1) and p-hydroxy-cinnamic acid (2), were subjected to systematic structure modifications, including various positions in luteolin segment for conjugation, different linkers (length, bond variation), as well as various substitutions in cinnamic acid segment (various substituents on benzene, and replacement of benzene by heteroaromatics and cycloalkane). Optimal conjugates such as 7c and 7k were chosen on the basis of a series of bioassay data for further investigation.

A dual-purpose strategy aimed at enhancing the binding affinity for microtubules and improving the water solubility of docetaxel led to the design and synthesis of a series of C-2- and C-3'-modified analogues. Both aims were realized when the C-3' phenyl group present in docetaxel was replaced with a propargyl alcohol. The resulting compound, 3f, was able to overcome drug resistance in cultured P-gp-overexpressing tumor cells and showed greater activity than docetaxel against drug-resistant A2780/AD ovarian cancer xenografts in mice. In addition, the considerably lower hydrophobicity of 3f relative to both docetaxel and paclitaxel led to better aqueous solubility. A molecular model of tubulin-bound 3f revealed novel hydrogen-bonding interactions between the propargyl alcohol and the polar environment provided by the side chains of Ser236, Glu27, and Arg320.

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 &beta, III-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 &beta, III 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 &beta, III.

Two β-secreatase (BACE1) inhibitors from natural products (cinnamic acid and flavone) were linked to furnish potent, cell permeable BACE1 inhibitors with noncompetitive mode of inhibition, with the assistance of saturated transfer difference (STD)-NMR technique. Some of these conjugates also exhibited selective BACE1 inhibition over other aspartyl proteases such as BACE-2 and renin, as well as poor cytotoxicity. Taken together, conjugates 4 represent a new series of BACE inhibitors warrants further investigation for their potential in Alzheimier's disease therapy.

Background: The development of antiangiogenic agents arises as a more effective and selective therapeutic approach for the treatment of cancer. In addition to reduced acute toxicity, the efficacy of chemotherapy could be improved when administered in combination specific antiangiogenic with cytotoxic agents. The conjugation or hybridization of bifunctional molecules is one of the alternative rational design strategies for co-administration of anticancer drugs. Objective and Methods: The goal of this work is to prepare the conjugates of an antiangiogenic triterpene, 3-oxo oleanolic acid, and structurally related triterpenoids with a cytotoxic semibenzoquinone, jacaranone. The cytotoxic, antiproliferative and antiangiogenic activities of segments and conjugates were determined. The possible targets of conjugates 6a-6h were predicted using Similarity Ensemble Approach (SEA). Results: The results showed that these conjugates are more potent in both cytotoxic and antiangiogenic assays than their corresponding parent molecules, and are also selectively more active against melanoma cells B16 and metastatic B16BL6 than the two other cancer cell lines (A549 and MCF-7) tested. The predicted antiangiogenesis related targets could involve glycogen phosphorylase, neuraminidase, interferon gamma, and tubulin beta chain. Conclusion: The bifunctional conjugates could be useful as dual acting antitumor/antigiogenic agents.

Tubulin has been shown to be an effective target for the development of cytotoxic agents against prostate cancer. Previously, we reported that Lx2-32c is an anti-tubulin agent with high binding affinity to tubulin. In this study, we investigated the potential of Lx2-32c to act as an effective cytotoxic agent in the treatment of prostate cancer. MTT assays showed that Lx2-32c was cytotoxic to all tested prostate cancer cell lines. The Lx2-32c-treated cells typically exhibited a rounded morphology associated with the onset of apoptosis, as evidenced by immunocytochemical staining. Human prostate cancer cell lines treated with Lx2-32c arrest in the G2/M phase of the cell cycle and the treatment is associated with an increased ratio of cells in the sub-G0/G1 phase as determined by flow cytometry. Furthermore, expression of the cleaved form of poly (ADP-ribose) polymerase in prostate cancer cell lines treated with Lx2-32c was shown by Western blotting assay. Xenograft implants of LNCaP and PC3-derived tumors in nude mice showed that Lx2-32c treatment significant inhibited tumor growth with effects equivalent to those of docetaxel. These findings demonstrate the potential of Lx2-32c as a candidate antitumor agent for the treatment of prostate cancer., Graphical abstract A novel microtubule-polymerizing agent, Lx2-32c, can arrest prostate cancer cells in the G2/M phase and induce cell apoptosis by disrupting microtubule dynamics. This compound also displays antitumor efficacy in vivo. fx1

A novel C,D-spirodioxene taxoid (6) was prepared from paclitaxel (1a), with the key steps including an unexpected Pd-mediated ring cyclization. The anti-tubulin activity of 6 was decreased relative to that of 1a and a previously reported C,D-spirolactone taxane (5). These observations could be rationalized on the basis of molecular modeling results. To the best of our knowledge, this is the first example indicating that 1,4-dioxenes can be synthesized from a mono-allyl vicinal diol through a Wacker-type cyclization. This strategy may be applicable to the synthesis of other C,D-spiro taxoids.

Triple negative breast cancer (TNBC) is a severe breast cancer subtype with the high mortality rate, and still is lack of effective therapeutic means so far. Aziditaxel, a water-insoluble compound, is a novel taxane derivative with strong anti-tumor activity. In this study, we constructed an aziditaxel-loaded nano drug delivery system using human serum albumin as a carrier, and further investigated its anti-tumor effect on TNBC in vitro. An emulsion solvent evaporation method was employed to prepare aziditaxel-loaded human serum albumin nanoparticles (AT-NPs). Their physicochemical properties were characterized according to morphology, particle size, zeta potential, reconstitution stability and in vitro drug release. The in vitro anti-tumor effects of AT-NPs on TNBC were evaluated using a 4T1 murine triple negative mammary cancer cell lines as the TNBC model. The results showed that AT-NPs could be effectively taken up by 4T1 cells in a time-dependent manner. Cell Counting Kit-8 assay showed that the IC50 of AT-NPs was 0.17 μg/ml. Meanwhile, compared with AT, AT-NPs had a better ability to promote apoptosis and induce G2/M cycle arrest. On the other hand, AT-NPs had significantly inhibitory effects on the 4T1 cell adhesion, migration and invasion with the respective average inhibition ratios of 32.53%, 83.26% and 75.78%. Thus, our study revealed that AT-NPs had favorable antitumor activity in vitro and exhibited a good prospect for application in the field of TNBC therapy.

53 p.-6 fig.-3 tab.-1 graf. Tang, Yong et al., 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 βIII-tubulin overexpression. Based on the structure of C-seco taxoid 1 m (IDN5390) which was believed to more selectively interact with βIII-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., This research was supported by NSFC (Grant No. 30930108) to (W.-S.F.), and by BIPPED2 (S2010/BMD-2457) (J.F.D.), project of the Comunidad de Madrid and the BIO2013-42984R (to J.F.D.) project from the Ministry of Economy and Competitiveness of Spain.

An efficient route for the semi-synthesis of either 1α- or 1β-OH epimers of 1-hydroxy-3-deoxyolean-12-en-28-oic acid (1), 6–8 steps from oleanolic acid is reported. The synthesis involves stereoselective formation of α,β-unsaturated epoxy ketone and subsequent Wharton reaction as key steps, offering a new access to the 1-O-substituted oleanolic acid-type pentacyclic triterpenoids.

The pentacyclic triterpene oleanolic acid (OA, 1) with known farnesoid X receptor (FXR) modulatory activity was modified at its C-3 position to find new FXR-interacting agents. A diverse substitution library of OA derivatives was constructed in silico through a 2D fingerprint similarity cluster strategy. With further docking analysis, four top-scored OA 3-O-ester derivatives were selected for synthesis. The bioassay results indicated that all four compounds 3 inhibited chenodeoxycholic acid (CDCA)-induced FXR transactivation in a concentration-dependent mode. Among them 3b and 3d are more active than the parent compound OA. A molecular simulation study was performed to attempt to explain the structure-activity relationship (SAR) and the antagonistic action. To the best of our knowledge, this is the first report on semi-synthetic pentacyclic triterpenoids with FXR-modulatory activities.

Farnesoid X receptor (FXR), a nuclear receptor mainly distributed in liver and intestine, has been regarded as a potential target for the treatment of various metabolic diseases, cancer and infectious diseases related to liver. Starting from two previously identified chalcone-based FXR antagonists, we tried to increase the activity through the design and synthesis of a library containing chalcones, flavones and chromenes, based on substitution manipulation and conformation (ring closure) restriction strategy. Many chalcones and four chromenes were identified as microM potent FXR antagonists, among which chromene 11c significantly decreased the plasma and hepatic triglyceride level in KKay mice.

Li-qing Chen, Wei Huang, Zhong-gao Gao, Wei-shuo Fang, Ming-ji Jin State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China Abstract: Lx2-32c is a novel taxane derivative with a strong antitumor activity. In this study, we developed Lx2-32c–loaded polymeric micelles (Lx2-32c-PMs) with small size and investigated their antitumor efficacy against tumor growth and metastasis on 4T1 murine breast cancer cell line with Cremophor EL–based Lx2-32c solution as the control. In this study, copolymer monomethoxy polyethylene glycol2000–polylactide1300 was used to prepare Lx2-32c-PMs by film hydration method, and their physicochemical properties were characterized as well, according to morphology, particle size, zeta potential, in vitro drug release, and reconstitution stability. Under confocal laser scanning microscopy, it was observed that Lx2-32c-PMs could be effectively taken up by 4T1 cells in a time-dependent manner. Cell Counting Kit-8 assay showed that the IC50 of Lx2-32c-PMs was 0.3827 nM. Meanwhile, Lx2-32c-PMs had better ability to promote apoptosis and induce G2/M cycle block and polyploidy formation, compared with Lx2-32c solution. More importantly, in vivo animal studies showed that compared to Lx2-32c solution, Lx2-32c-PMs possessed better ability not only to effectively inhibit the tumor growth, but also to significantly suppress spontaneous and postoperative metastasis to distant organs in 4T1 orthotopic tumor-bearing mice. Consequently, Lx2-32c-PMs have significantly prolonged the survival lifetime of tumor-bearing mice. Thus, our study reveals that Lx2-32c-PMs had favorable antitumor activity and exhibited a good prospect for application in the field of antitumor therapy. Keywords: Lx2-32c, micelles, small size, 4T1 mammary carcinoma, tumor therapy, metastasis

High precision 3D sculpture model can take the accurate records of the shape, material and color on the surface of the sculpture. It is an important foundation work of digital documentation, preservation, archaeological research and analysis for the sculpture types of cultural heritage. Constructing high precision 3D sculpture model includes two aspects: geometry modeling and texture reconstruction. But, there are many urgent problems still existing in the method of high precision texture reconstruction. This paper discussed a method of high precision texture reconstruction based on non-rigid transformation for 3D sculpture model. First, coarse registration of texture image to geometrical model is conducted with direct linear transformation (DLT) method. Then, the registration is optimized with thin plane spline (TPS) function to reduce local matching errors between texture image and geometrical model. Finally, texture mapping is implemented with optimized registration result. The experiments based on the sculpture in Dunhuang Mogao Grottoes of China are conducted, and the efficiency and feasibility of the proposed methods are proved.

Resistance to anticancer drugs is a major obstacle to successful chemotherapy. Thus, the exploration of new drugs and strategies in combating resistance is of great importance. In this study, we investigated the anti-tumor drug resistance (anti-resistance for short) activity of Lx2-32c, a novel taxane, and its possible mechanisms. Lx2-32c was cytotoxic to various drug-resistant tumor cell lines, and significantly suppressed the growth of tumor xenografts in paclitaxel-resistant MX-1 nude mice. It promoted microtubule polymerization and G(2)/M phase arrest in MX-1/T cells. Moreover, it induced typical apoptotic characteristics indicated by morphological changes and DNA fragmentation. Apoptosis was associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c and apoptosis-inducing factor (AIF) release, elevation of the Bax/Bcl-2 ratio, activation of caspase-9,-3 but not caspase-8 and Fas/FasL, and degradation of poly(ADP-ribose) polymerase (PARP). In conclusion, Lx2-32c is an effective microtubule-stabilizing agent in overcoming paclitaxel resistance by inducing apoptosis via the intrinsic apoptotic pathway. It also displayed robust anti-paclitaxel-resistance activity in vivo. Therefore, these findings provide new insight into the strategy to overcome resistance by manipulating dysregulated apoptosis pathway.

4 p.-1 fig.-1 tab.-6 schem., To probe the exact role of the oxetane D ring in both tubulin binding and cytotoxicity of taxanes, novel D-seco taxanes bearing a C4 ether substituent have been prepared from paclitaxel 1a. Among them, 20-hydroxymethyl-4-allyloxy D-seco taxane 5e is the most active in both tubulin and cytotoxicity assays. It is only slightly less potent than 1a on tubulin polymerization promotion in vitro and the most cytotoxic among all D-seco taxanes known to date. The reason for the loss and restoration of bioactivity for these D-seco taxanes is also discussed with the assistance of NMR and molecular modeling studies. From these results, we draw a conclusion that the intact D ring of taxanes is not strictly necessary for their binding to tubulin and cytotoxic effects., S.R.W. and W.S.F. thank the National Natural Science Foundation of China (Grant Nos. 30930108 and 81202434)for financial support. F.G. is grateful to the Spanish Ministerio de Economıa y Competitividad (SAF2012-39760-C02-02) and Comunidad Autónoma de Madrid (S2010-BMD-2457).

Several pieces of experimental evidence led us to hypothesize that the mechanism of action of paclitaxel (Taxol) could involve a two-steps binding process, with paclitaxel first binding within the outer wall of microtubules and then moving into the inner binding site. In this work, we first used multiply targeted molecular dynamics (MTMD) for steering paclitaxel from the outer toward the inner binding site. This rough trajectory was then submitted to a refinement procedure in the path collective variables space. Paclitaxel binding energy was monitored along the refined pathway, highlighting the relevance of residues belonging to the H6-H7 and the M- loops. Computational results were supported by kinetics studies performed on fluorescent paclitaxel derivatives.

Three new C-glucosylanthrones, 3′-O-acetyl-5-hydroxylaloin A (2), 2′,6′-O-diacetyl-5-hydroxylaloin A (4), and 4′,6′-O-diacetyl-5-hydroxylaloin A (5), along with three known compounds, 5-hydroxyaloin A (1), 6′-acetyl-5-hydroxylaloin A (3), and 4-methoxy-6-(2′,4′-dihydroxy-6′-methylphenyl)-pyran-2-one (6), were isolated from the leaves of Aloe nobilis, and their structures were elucidated on the basis of spectroscopic evidences. Compounds 1, 2, 4 and 5 showed antioxidant activity with inhibitory rates of 31.0, 34.0, 34.0, and 42.0%, respectively, at 10− 5 M.

The pore site in microtubules has been studied with the use of Hexaflutax, a fluorescent probe derived from paclitaxel. The compound is active in cells with similar effects to paclitaxel, indicating that the pore may be a target to microtubule stabilizing agents. While other taxanes bind microtubules in a monophasic way, thus indicating a single type of sites, Hexaflutax association is biphasic. Analysis of the phases indicates that two different binding sites are detected, reflecting two different modes of binding, which could arise from different arrangements of the taxane or fluorescein moieties in the pore. Association of the 4-4-20 antifluorescein monoclonal antibody-Hexaflutax complex to microtubules remains biphasic, thus indicating that the two phases observed arise from two different poses of the taxane moiety., This work was supported in part by grant BIO2007-61336 from the Ministry of Science and Innovation to J.F.D., BIPPED-CM from Comunidad de Madrid to J.F.D. and J.M.A., and grant MOST No. 2006DFA31490 to W.S.F.

A dual strategy aimed at enhancing the binding affinity for microtubules and improving the water solubility of docetaxel led to the design and synthesis of a series of novel C-2 and C-3' modified analogs. Among the latter, a compound demonstrated a higher affinity constant for microtubules that resulted in the ability to overcome resistance in cultured P-gp overexpressing tumor cells and a superior activity to docetaxel in drug-resistant A2780/AD ovarian cancer cells xenografted in mice. In addition, the considerably lower hydrophobicity of this compound relative to both docetaxel and paclitaxel led to a 3-fold better aqueous solubility. A molecular modelling was performed to explain its potent activity at structural level. Citation Format: Weishuo Fang, Hongbo Wang, Federico Gago. Potent and water-soluble C-3’ modified docetaxel analogs by enthalpic driven optimization [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A076.

A new triglucosylated naphthalene derivative, named aloveroside A (1), together with two known anthraquinone dimers and two 6-phenyl-2-pyrone derivatives, was isolated from the Aloe vera ethanolic extracts. The structure of 1 was established as 1-(((4-(1-O-beta-D-glucopyranosyl -(1-->4)-beta-D-xylopyranoside)-hydroxymethyl)-1-hydroxy-8-O-alpha-L-rhamnopyranoside)naphthalene-2-yl)-ethanone by means of spectroscopic evidences and chemical methods. All these compounds were tested for their BACE inhibitory activity but no significant activities were found.

Microtubules are very important targets for cancer chemotherapy. During the past 15 years, three structurally diverse classes of microtubule stabilising agents (MSAs), namely, taxanes, epothilones and discodermolides, have been approved as anticancer agents or subjected to clinical trials, and many novel MSAs have also been identified.This review focuses on recent advances in the use of taxanes, epothilones and discodermolides, as well as some recently described natural product based MSAs.Data were identified through the search of PubMed for research articles and reviews, the website of European patents ( http://ep.espacenet.com ) and US patents ( www.uspto.gov ) for patents up to October 2008. Only well-established MSAs are mentioned in this review.Great advances have been made in the application of MSAs in antitumour clinical practice and drug discovery. Many structure-activity relationship studies of MSAs as novel anticancer drugs have been conducted in recent years. To enhance the efficacy of MSAs as clinically useful therapeutics, numerous efforts have been made in combination chemotherapy regimens and include: i) the combination of structurally different MSAs, ii) combination of MSAs with other classes of anticancer agent with a different mechanism of action and iii) novel ways of administrating well-established MSAs.

Bioassay-guided fractionation of the ethanolic extract of Senecio scandens led to the isolation of four new compounds 4, 5, 7, and 8, along with four known jacaranone analogs (1, 2, 3, 6). Their structures were elucidated on the basis of spectral and chemical evidence. Compound 7 was obtained as a tautomeric mixture of alpha/beta-epimer. The cytotoxic activities of these compounds were evaluated. Among these, compounds 5 and 8 showed potent cytotoxicities. The benzoquinone derivative, jacaranone ethyl ester (1), was the major cytotoxic constituent in this plant with IC(50)s at a range of 0.5-1.0 microg/ml against various tumor cell lines. The SAR of these jacaranone analogs (1-8), isolated from S. scandens, was also discussed.

An efficient partial synthesis of 25-acetoxy-3alpha-hydroxyolean-12-en-28-oic acid (1), starting from oleanolic acid (2), has been developed in an efficient manner (13 steps, 21% yield), employing a photochemical reaction of nitrite 8 for the introduction of C-25 substituting group as the key step. Based on the comparison of its spectral data with those reported for compound 1 isolated from Liquidamber styraciflua, we found the structure in that paper was incorrectly assigned, and should be revised as 3alpha-acetoxy-25-hydroxyolean-12-en-28-oic acid (15).

Bioassay guided fractionation of Boenninghausenia sessilicarpa (Rutaceae) resulted in the isolation of a new dimeric coumarin glucoside 9'-methoxyl rutarensin (1) and a cytotoxic compound rutamarin (4), as well as an antivirus component leptodactylone (8), together with six known coumarins. Their structures were elucidated by 1D- and 2D NMR spectroscopy and ESI-MS analyses, respectively. Rutamarin (4) showed significant inhibitory activities against A-549, Bel-7402, HepG-2 and HCT-8 tumour cell lines with IC50s of 1.318, 2.082, 2.306 and 2.497 microg/ml. In addition, leptodactylone (8) showed potent protective activity on cells infected by SARS-CoV with ratio of 60% at 100 microg/ml.

Two novel compounds( 4 a and 4 b) were obtained by the association of 2, 2, 4-trimethyl-3-hydroxy-5-cyclohexenecarboxylate with ( S )-isoserine derivatives. The space location of the hydroxyl group of compound 1 was identified via the formation of lactone 6 . Fe 2 (SO 4 ) 3 · χH 2 O was used as the catalyst for the synthesis of lactone 6 . The carboxyl group was selectively protected with diazomethane. All the products were characterized via 1 H NMR and mass spectra. The Docking study showed that the associations have the potential therapeutic use of DPP-IV inhibitor.

[reaction: see text] Two new iridoid glucoside tetramers, dipsanosides A (1) and B (2), the first-reported iridoid tetramers with four glucosides, were isolated from Dipsacus asper. Their structures were determined by analysis of 1D and 2D NMR data as well as by comparison with model compounds. Their cytotoxicities were tested, but neither of them showed obvious activity.

Structure activity relationship (SAR) and mechanism of paclitaxel and its analogues in recent years are discussed in the following areas: SAR of paclitaxel analogues toward "normal" and multi-drug resistance tumors; paclitaxel prodrugs with improved water solubitily and specificity; mechanism of paclitaxel related to tubulin binding and quest for its pharmacophore.

49 p.-7 tab.- 7 fig., We have found that four taxanes with chemical modifications at positions C10 and C13 were active against all types of taxane resistant cell lines, resistant by p-Gp overexpression, by mutations in the β-tubulin binding site or by overexpression of the highly dynamic βIII-tubulin isotype. We have characterized the interaction of taxanes with high activity on chemotherapy resistant tumoural cells with microtubules, and also studied their cellular effects. The biochemical property enhanced in comparison with other taxanes is their potency at inducing tubulin assembly, despite the fact that their interactions with the microtubule binding sites (pore and luminal) are similar as studied by NMR and SAXS. A differential interaction with the S7-S9 loop (M-loop) is responsible for their enhanced assembly induction properties. The chemical changes in the structure also induce changes in the thermodynamic properties of the interaction, indicating a higher hydrophilicity and also explaining their properties on p-Gp and βIII overexpressing cells and on mutant cells. The effect of the compounds on the microtubular network is different from those observed with the classical (docetaxel and paclitaxel) taxanes, inducing different bundling in cells with microtubules being very short, indicating a very fast nucleation effect and reflecting their high assembly induction power., This research was supported by BIPPED2 (S2010/BMD‐2457) (JFD), and MHit (CAM S2010/BMD-2353 to JJB) projects of the Comunidad de Madrid, the BIO2010‐16351 (to JFD) and CTQ2012-32025 (to JJB) projects from the Ministry of Economy and Competitiveness of Spain, a NSFC grant (No. 30930108) to (WF), the NIH/NCI CA103314 project (to IO) and a Ramon y Cajal grant to Dr. A. Canales.

Lx2-32c is a novel taxane that has been demonstrated to have robust antitumor activity against different types of tumors including several paclitaxel-resistant neoplasms. Since the delivery vehicles for taxane, which include cremophor EL, are all associated with severe toxic effects, liposome-based Lx2-32c has been developed. In the present study, the pharmacokinetics, biodistribution, antitumor efficacy and safety characteristics of liposome-based Lx2-32c were explored and compared with those of cremophor-based Lx2-32c. The results showed that liposome-based Lx2-32c displayed similar antitumor effects to cremophor-based Lx2-32c, but with significantly lower bone marrow toxicity and cardiotoxicity, especially with regard to the low ratio of hypersensitivity reaction. In comparing these two delivery modalities, targeting was superior using the Lx2-32c liposome formulation; it achieved significantly higher uptake in tumor than in bone marrow and heart. Our data thus suggested that the Lx2-32c liposome was a novel alternative formulation with comparable antitumor efficacy and a superior safety profiles to cremophor-based Lx2-32c, which might be related to the improved pharmacokinetic and biodistribution characteristics. In conclusion, the Lx2-32c liposome could be a promising alternative formulation for further development.

Base-promoted C-7 epimerizations of paclitaxel, 10-deacetylbaccatin III were investigated. It has been found that 13α-OH may play an important role in the equilibrium of C-7 epimers of paclitaxel and related taxoids.

The major mechanism of action of antitumor taxanes, including two clinically useful antitumor agents, paclitaxel and docetaxel, lies in their interactions with β-tubulin in microtubule polymers, leading to cell cycle arrest and apoptosis. However, owing to the technical limitations, the molecular interactions of ligands with the residues in taxane binding sites of tubulin as well as the conformations adopted by taxanes on binding are still not fully understood.This review focuses on the exploration of paclitaxel's interactions with tubulin, and the impact of such efforts on the drug discovery for new taxanes and microtubule stabilizing agents (MSAs).Data were identified through the search of Chemical Abstracts and PubMed databases for research articles and reviews up to April 2008.Based on a collection of information gathered from crystallography, 1D and 2D NMR spectroscopy (NOESY, ROESY, REDOR), and structural-activity relationship (SAR) by chemical synthesis and pharmacological assays, 'opened' or T-shape conformations have been predicted to be the biologically active ones in recent years, and confirmed by further SAR studies. Some more potent analogues than paclitaxel or simplified compounds with similar potencies to that of paclitaxel have been discovered. Structural studies of taxol analogues will continue to make great contributions to the rational design of taxanes and novel prototype MSAs for drug discovery.

Ten novel taxanes bearing modifications at the C2 and C13 positions of the baccatin core have been synthesized and their binding affinities for mammalian tubulin have been experimentally measured. The design strategy was guided by (i) calculation of interaction energy maps with carbon, nitrogen and oxygen probes within the taxane-binding site of β-tubulin, and (ii) the prospective use of a structure-based QSAR (COMBINE) model derived from an earlier series comprising 47 congeneric taxanes. The tubulin-binding affinity displayed by one of the new compounds (CTX63) proved to be higher than that of docetaxel, and an updated COMBINE model provided a good correlation between the experimental binding free energies and a set of weighted residue-based ligand-receptor interaction energies for 54 out of the 57 compounds studied. The remaining three outliers from the original training series have in common a large unfavourable entropic contribution to the binding free energy that we attribute to taxane preorganization in aqueous solution in a conformation different from that compatible with tubulin binding. Support for this proposal was obtained from solution NMR experiments and molecular dynamics simulations in explicit water. Our results shed additional light on the determinants of tubulin-binding affinity for this important class of antitumour agents and pave the way for further rational structural modifications. © The Royal Society of Chemistry 2013., National Natural Science Foundation of China (NSFC grant 30930108 to W.S.F.); Spanish Ministerio de Ciencia e Innovación (BIO2008-04384 and BIO-2010-16351); Comisión Interministerial de Ciencia y Tecnología (SAF2009-13914-C02-02), and Comunidad de Madrid (S-BIO/0214/2006 and S2010-BMD-2457)

5 páginas, 3 figuras, 3 tablas, 1 esquema -- PAGS nros. 11062-11066, Deacetylcolchicine was reacted with substituted benzyl halides to provide a library of compounds for biological analysis. Compound 7 (3,4-difluorobenzyl-N-aminocolchicine) was shown to possess cytotoxicity in cancer cell lines in the low nanomolar range. Significantly, it showed no loss of activity in the resistant A2780AD ovarian carcinoma cell line known to overexpress the ABCB1 drug transporter and was also unaffected by overexpression of class III β-tubulin in HeLa transfected cells, K.P. was supported by YCR Program Grant, EPSRC Science Bridge (Grant EP/G042365/1), FCT (Grant SFRH/BD/46871/2008) and J.F.D. by Grant BIO2010-16351 from Ministerio de Economia y Competitividad and Grant S2010/BMD-2457 BIPEDD2 from Comunidad Autónoma de Madrid, Spain. Parental HeLa and transfected β-III cervix carcinoma cell lines were a kindly gift from Prof. Richard F. Ludueña (Biochemical Dept., The University of Texas Health Science Center, TX, U.S.)

Two new bicyclic taxane diterpenoids, taxachitrienes A(1) and B(2), were isolated from the needles of Taxus chinensis. Their structure were elucidated on the basis of spectroscopic data. The crystal structure of 2 was also presented. It is the first time for the isolation of bicyclic diterpenoid which is proposed as the biogenetic precursor for taxanes.