Cytotoxic properties of the alkaloid rutaecarpine and its oligocyclic derivatives and chemical modifications to enhance water-solubility

The alkaloid rutaecarpine and its derivatives have been described as cytotoxic and hold potential as antitumor agents. Nevertheless, their synthesis is demanding and compounds display poor water solubility. Herein, we describe the synthesis of two sets of rutaecarpine derivatives with amine functions to improve solubility. Using a classic shake-flask experiment and a potentiometric titration platform, the water solubility of the compounds was determined. Solubility improved significantly with the amine functions connected over the indole-N atom. Reduction of metabolic activity and cell viability on HeLa cells was in the same range or better for these derivatives compared to the chemically unaltered parent compounds prepared in a new synthetic procedure established in our group.     

Facile synthesis of thiol-reactive Cy3 and Cy5 derivatives with enhanced water solubility

The cyanine dyes Cy3 and Cy5 have proven valuable in numerous applications involving conjugation with proteins. Practical syntheses of lysine-selective, succinimidyl ester derivatives of these dyes have been published, and succinimidyl esters are commercially available. However, the published syntheses of cysteine-selective derivatives produce relatively low yields from expensive starting materials, or produce molecules with marginal water solubility for protein labeling. We report here facile syntheses (four steps, >50% overall yield) of iodoacetamide, sulfhydryl-reactive derivatives of the Cy3 and Cy5 fluorophores. These novel derivatives have good water solubility (>2.5 mM) and bear only one reactive side chain, reducing possible protein cross-linking encountered with previous derivatives.     

New ionic derivatives of betulinic acid as highly potent anti-cancer agents

Betulinic acid is a natural compound with high in vitro cytotoxicity toward many cancer cells. However, the poor water solubility of this compound hampers an effective in vivo cancer study. We prepared new ionic derivatives of betulinic acid with higher water solubilities, without losing the structural integrity and functionality of this compound. As a result, these new ionic derivatives have shown much higher inhibitory effects against different cancer cell lines such as melanoma A375, neuroblastoma SH-SY5Y and breast adenocarcinoma MCF7. For A375 cell lines, the derivative 5 exhibited a low IC(50) value of 36 μM (vs 154 μM for betulinic acid); for MCF7 cell lines, the derivative 5 also exhibited a low IC(50) value of 25 μM (vs 112 μM for betulinic acid). The high cytotoxicity of these new derivatives can be linked to their greatly improved water solubility. Our assay method used little DMSO in aiding the dissolution of these derivatives to demonstrate the advantage of improved water solubility and to mimic the in vivo study conditions. The cell viability studies based on both MTT and LDH assay methods have confirmed the high inhibitory effect of our ionic derivatives of betulinic acid (particularly 4 and 5) against different cancer cells.     

Synthesis and cytotoxicity of novel indirubin-5-carboxamides

Indirubins have been reported to act as potent inhibitors of protein kinases relevant to tumorigenesis and of tumor cell growth, but their development to antitumor drugs suffer from their poor water solubility. We synthesized a novel class of indirubin derivatives, indirubin-5-carboxamides, carrying amide substituents with basic centers. Quaternization or protonation of these alkylamino substituents provided indirubins with significantly improved solubility without loss of bioactivity.     

Synthesis and antiviral evaluation of C-4-hydrazide derivatives of 2',3'-dideoxycytidine

Syntheses of three hitherto unknown derivatives of 2',3'-dideoxycytidine, namely C-4-(salicylic hydrazide)-ddC, C-4-(N-butyloxycarbonyl-isoleucine hydrazide)-ddC and its N-unprotected chlorhydrate salt have been carried out. These compounds do not induce inhibition of HIV-1 replication in cell culture experiments. Nevertheless, the modifications on the base moiety increased in all cases the lipophilicity of the parent molecule with an acceptable water solubility compared to ddC.     

Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part 2: synthesis of potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists

We synthesized 4-aminopiperidine derivatives of our prototype integrin alpha(v)beta3 antagonist 1 in an attempt to increase the activity and water solubility. Introduction of one or two hydrophilic moieties into the central aromatic ring and/or the benzene ring at the C-terminus of 1 increased water solubility and enhanced inhibition of cell adhesion. The results of a structure-activity relationships (SAR) study indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for alpha(v)beta3 receptor binding activity. Some of these compounds are novel and potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile.     

Preparation of amino acid conjugates of betulinic acid with activity against human melanoma.

Betulinic acid has been coupled with a series of amino acids at C-28 carboxylic acid position and the toxicity of the derivatives has been evaluated against cultured human melanoma (MEL-2) and human epidermoid carcinoma of the mouth (KB) cell lines. A number of amino acid conjugates of betulinic acid showed improved water solubility as well as selective cytotoxicity. This investigation demonstrates that amino acid conjugates of betulinic acid can produce potentially important derivatives, which may be developed as antitumor agents.     

Analogues of hexamethylmelamine. The anti-neoplastic activity of derivatives with enhanced water solubility.

The preparation of some water soluble analogues of the tumour growth inhibitory hexamethylmelamine is described. The ultra-violet absorption characteristics, solubility and n-octanol/water partition coefficients of these new derivatives and some related compounds have been determined. Rates of demethylation by a liver microsomal preparation and anti-tumour assays against the ADJ/PC6A mouse plasma cell tumour and a human lung tumour xenograft are reported. Two of the derivatives, pentamethylmelamine and N2, N4, N6-trimethyl-N2, N4, N6-trimethylolmelamine, which have shown activity against the xenograft are potential candidates for clinical trials using the intravenous route of administration.     

Correlation of structure to antitumor activities of five derivatives of a beta-glucan from Poria cocos sclerotium

A water-insoluble (1-->3)-beta-D-glucan isolated from fresh sclerotium of Poria cocos was, respectively, sulfated, carboxymethylated, methylated, hydroxyethylated, and hydroxypropylated, to afford five water-soluble derivatives. Their weight-average molecular masses (Mw) and intrinsic viscosities ([eta]) were determined by size-exclusion chromatography combined with laser light scattering (SEC-LLS), LLS, and viscometry in phosphate buffer solution (PBS) at 37 degrees C. The antitumor activities, against Sarcoma 180 tumor cell (S-180) and gastric carcinoma cell strain (MKN-45 and SGC-7901) of the native beta-glucan and the five derivatives, were tested in vitro and in vivo. The Mw values of the five derivatives in PBS were determined to be 3.8 x 10(4), 18.9 x 10(4), 16.0 x 10(4), 76.8 x 10(4), and 224.3 x 10(4), respectively. The high Mw values of the hydroxyethylated and hydroxypropylated derivatives in aqueous solution resulted from aggregation, and their true Mw values obtained in dimethyl sulfoxide were 20.1 x 10(4) and 19.1 x 10(4). The sulfated and carboxymethylated derivatives having DS of 1.0-1.3 show good water solubility, and exist as relatively expanded chains in aqueous solution. Interestingly, the native beta-glucan did not show antitumor activity, whereas the sulfated and carboxymethylated derivatives exhibit significant antitumor activities against S-180 and gastric carcinoma tumor cells. This work showed that good water solubility, relatively high chain stiffness, and moderate molecular mass of the derivatives in aqueous solution contribute beneficial to enhancement of antitumor activity.     

SYNTHESIS AND ANTIVIRAL EVALUATION OF C-4-HYDRAZIDE DERIVATIVES OF 2′,3′-DIDEOXYCYTIDINE

Syntheses of three hitherto unknown derivatives of 2′,3′-dideoxycytidine, namely C-4-(salicylic hydrazide)-ddC, C-4-(N-butyloxycarbonyl-isoleucine hydrazide)-ddC and its N-unprotected chlorhydrate salt have been carried out. These compounds do not induce inhibition of HIV-1 replication in cell culture experiments. Nevertheless, the modifications on the base moiety increased in all cases the lipophilicity of the parent molecule with an acceptable water solubility compared to ddC.     

Synthesis of puromycin derivatives with backbone-elongated substrates and associated translation inhibitory activities

We have synthesized a series of 5′-phosphorylated and 5′-cytidylyl-(3′–5′)-cytidylyl-(3′–5′)-puromycin derivatives that have backbone-elongated substrates. All the synthesized puromycin derivatives showed good solubility in water and were applied to translation inhibitory assay in a reconstituted Escherichia coli translation system.     

Synthesis and evaluation of ursolic acid derivatives as potent cytotoxic agents

Structural modification was performed at the C-3 and C-28 positions of ursolic acid (UA). Ten UA derivatives with distinct electrical property were synthesized. They could be divided into two groups according to their charge under physiological conditions: (1) Group I negatively charged and (2) Group II positively charged. The anti-proliferative capability of the derivatives was evaluated against HepG2, AGS, HT-29 and PC-3 cells by the MTT assay. Flow cytometry and Annexin V/PI dual staining assay were carried out to explore the antitumor mechanism. The results showed the cytotoxic capacity of the compounds was: Group I相似文献   

Rich spectroscopic and molecular dynamic studies on the interaction of cytotoxic Pt(II) and Pd(II) complexes of glycine derivatives with calf thymus DNA

Some amino acid derivatives, such as R-glycine, have been synthesized together with their full spectroscopic characterization. The sodium salts of these bidentate amino acid ligands have been interacted with [M(bpy)(H₂O)₂](NO₃)₂ giving the corresponding some new complexes with formula [M(bpy)(R-gly)]NO₃ (where M is Pt(II) or Pd(II), bpy is 2,2′-bipyridine and R-gly is butyl-, hexyl- and octyl-glycine). Due to less solubility of octyl derivatives, the biological activities of butyl and hexyl derivatives have been tested against chronic myelogenous leukemia cell line, K562. The interaction of these complexes with highly polymerized calf thymus DNA has been extensively studied by means of electronic absorption, fluorescence and other measurements. The experimental results suggest that these complexes positive cooperatively bind to DNA presumably via groove binding. Molecular dynamic results show that the DNA structure is largely maintained its native structure in hexylglycine derivative–water mixtures and at lower temperatures. The simulation data indicates that the more destabilizing effect of butylglycine is induced by preferential accumulation of these molecules around the DNA and due to their more negative free energy of binding via groove binding.     

Encapsulation of Acetylshikonin by Polyamidoamine Dendrimers for Preparing Prominent Nanoparticles

Acetylshikonin (AS) has demonstrated antitumor potential. However, the development of therapeutic applications utilizing AS is inhibited by its poor solubility in water. In the present work, polyamidoamine (PAMAM) dendrimers and their PEGylated derivatives were employed to increase the solubility of AS. A distinct color transition was observed during the encapsulation of AS suggesting strong intermolecular forces between PAMAM and AS. Ultraviolet–visible, high-performance liquid chromatography, and ¹H NMR were used to verify the interaction between PAMAM and AS. The maximum amount of combined AS to each PAMAM molecule was determined. The cytotoxicity of AS nanoparticles was evaluated against leukemia (K562) and breast cancer (SK-BR-3) cell lines; the AS nanoparticles were shown to effectively inhibit tumor cells.     

天然抗脑缺血药物丁苯酞类衍生物的研究进展

丁苯酞 (NBP) 是我国研制的具有自主知识产权的抗脑缺血药物,具有抗血小板聚集、抗血栓、减轻脑水肿等多种生物活性。但其 总体疗效不高,且极难溶于水,限制了其在临床上广泛应用,故研究人员对其进行了多方面的结构修饰与改造。综述近年来对 NBP 的结构 改造及其衍生物的研究进展,旨在为该类药物进一步研发提供参考。     

Synthesis,biodistribution and antitumor activity of hematoporphyrin-platinum(II) conjugates

A new series of platinum(II) complexes of pegylated hematoporphyrin derivatives with controlled hydrophobic/hydrophilic balance were synthesized by introducing different kinds of poly(ethylene glycol) and amine ligands to the porphyrin ring. The antitumor activity of the porphyrin-platinum(II) conjugates was assayed in vitro and in vivo against leukemia L1210 cell line and various human tumor cell lines. The present complexes exhibited high antitumor activity and improved water solubility as well as considerable lipophilicity. In particular, complex 16 showed not only higher in vivo activity (T/C%=258) than cisplatin (T/C%=184) and carboplatin (T/C%=168), but also excellent solubility in water and organic solvent. The antitumor activity of complex 20 was superior to that of carboplatin against all human tumor cell lines tested. Moreover, some amphiphilic complexes (7 and 12) exhibited elevated tumor-localizing effect (tumor/muscle ratio>2).     

Design,synthesis and biological evaluation of novel stilbene-based antitumor agents

A series of novel stilbene derivatives has been synthesized and studied with the main goal to investigate SAR of the amino compound 1a, as well as to improve its water solubility, a potentially negative aspect of the molecule that could be a serious obstacle for a pre-clinical development. We have obtained derivatives with good cytotoxic activity, in particular, the derivatives 5c and 6b could represent two novel leads for further investigation. Compound 8b, a morpholino-carbamate derivative, prodrug of 1a, has a very good solubility in water, and is active in suppressing growth of tumor cells at a concentration of 5000 nM, which is a concentration 100 times higher than the parent stilbene 1a.     

Monodisperse oligoethylene glycols modified Camptothecin, 10-Hydroxycamptothecin and SN38 prodrugs

Camptothecin, which represents a class of natural products with high anticancer activity, suffers low water solubility which hampers its clinic application. To address this issue, monodisperse polyethylene glycols were employed to modify this class of natural products, including Camptothecin, 10-Hydroxycamptothecin, and SN38. Through selective modification with a series of monodisperse polyethylene glycols, 31 Camptothecin derivatives, including 9 ethers and 22 carbonates, were prepared using a macrocyclic sulfate-based strategy with high efficacy. Monodisperse polyethylene glycols modification provided the Camptothecin derivatives with high purity and fine-tunable water solubility. Through the physicochemical and biological assays, a few novel prodrugs with good solubility, cytotoxicity, and valuable drug release profile were identified as promising anticancer drug candidates.     

Synthesis and biological evaluation of novel conjugates of podophyllotoxin and 5-FU as antineoplastic agents

A series of novel conjugates of podophyllotoxin and 5-FU were designed using association strategy and were synthesized by coupling 4′-demethylepipodophyllotoxin with 5-FU-N¹-alkyl amino acid ester. These derivatives have been evaluated for cytotoxicity in vitro against tumour cell lines (HL-60, K562, A-549 and AGS), and their octanol–water partition coefficients (log P) were also determined. As compared with VP-16, most compounds showed superior water solubility, as well as more potent inhibitions against these four tumour cell lines. Compound 21 showed interaction with calf thymus DNA, and it was relatively resistant to metabolism by human plasma.     

Sulfamic and succinic acid derivatives of 25-OH-PPD and their activities to MCF-7, A-549, HCT-116, and BGC-823 cell lines

In the search for new anti-tumor agents with higher potency than our previously identified compound 1 (25-OH-PPD, 25-hydroxyprotopanaxadiol), 12 novel sulfamic and succinic acid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 1, compounds 2, 3, and 7 exhibited higher cytotoxic activity on A-549 and BGC-823 cell lines, together with lower toxicity in the normal cell. In particular, compound 2 exhibited the best anti-tumor activity in the in vitro assays, which may provide valuable data for the research and development of new anti-tumor agents.