Synthesis, acute toxicities, and antitumor effects of novel 9-substituted beta-carboline derivatives

A series of novel 9-substituted beta-carboline derivatives was synthesized from harmine and l-tryptophan, respectively. Cytotoxic activities of these compounds in vitro were investigated. The results showed that most compounds of 9-substituted beta-carboline derivatives had more remarkable cytotoxic activities in vitro than their corresponding parent compounds. Acute toxicities and antitumor effects of the selected beta-carboline derivatives in mice were also examined. The results demonstrated that a short alkyl or benzyl substituent at position-9 increased the antitumor activities significantly and a ethoxycarbonyl or carboxyl substituent at position-3 reduced the acute toxicity and neurotoxicity of these beta-carboline derivatives dramatically. Moreover the compounds both with an alkoxycarbonyl or carboxyl substituent at position-3 and a short alkyl or benzyl substituent at positon-9 exhibited more significant antitumor activities and lower acute toxicities and neurotoxicities than the other compounds. The compound 8c, having an n-butyl and a carboxyl substituent at position-9 and 3, respectively, was found to have the highest antitumor effect and the lowest acute toxicity and neurotoxicity. These data suggested that (1) appropriate substituents at both position-9 and 3 of beta-carboline derivatives might play a crucial role in determining their enhanced antitumor activities and decreased acute toxicities and neurotoxic effects; (2) the beta-carboline derivatives have the potential to be used as antitumor drug leads.     

Synthesis of phenanthroindolizidine alkaloids and evaluation of their antitumor activities and toxicities

We previously reported that phenanthroindolizidine alkaloid 3 and its derivatives had markedly potent in vitro cytotoxicity. However, they had low in vivo antitumor activities and high in vivo toxicities, which was a serious problem. To address this problem, new phenanthroindolizidine derivatives were synthesized and their antitumor activities and toxicities were evaluated. This study describes the relationship between the chemical structures, antitumor activities, and toxicities of these phenanthroindolizidine derivatives. Based on its properties, compound 8 was found to be the most suitable potential antitumor agent.     

Synthesis of 1-beta-D-ribofuranosyl-1,2-dihydropyrimidin-2-one derivatives and their biological activities

Several alkyl substituted 1-beta-D-ribofuranosyl-1,2-dihydropyrimidin-2-one derivatives were synthesized by the method of stannic chloride-catalyzed glycosidation method to elucidate their inhibitory activity of cytidine deaminase and also their antitumor activities in vitro and in vivo. Alkyl substitution at position 4 or 6 of the derivatives decreased their inhibitory activity for cytidine deaminase and also decreased antitumor activity against L1210 cells in vitro.     

Novel angular furoquinolinones bearing flexible chain as antitumor agent: design, synthesis, cytotoxic evaluation, and DNA-binding studies

A series of novel N-substituted angular furoquinolinone derivatives were synthesized and evaluated for their antitumor activities against QGY, K562, HeLa, P388, and A549 cell lines in vitro. The derivatives bearing basic amino side chain showed an improved antitumor activity. Compound 5h N-(2-dimethylamino-ethyl)-2-(4,8,9-trimethyl-2-oxo-2H-furo[2,3-h]quinolin-1-yl)-acetamide exhibited the highest activities against P388 and A549 cell lines, which are evidenced by the IC(50) values that are four to five fold lower than that for unsubstituted parent compound. DNA-binding experiments suggested that these derivatives bind to DNA through intercalation.     

Novel synthetic isoquinolino[5,4-ab]phenazines: inhibition toward topoisomerase I, antitumor and DNA photo-cleaving activities

The novel DNA interactive isoquinolino[5,4-ab]phenazine derivatives were designed and synthesized. Their inhibitory abilities toward topoisomerase I, antitumor activities and DNA photo-cleaving abilities were examined. The substituents at peri sites of two phenazine N atoms played very important roles for all these biological activities. At a concentration of 100 microM, all these phenazine derivatives (but A2 and A6) exhibited an inhibitory activity toward topoisomerase I. A6 had efficient antitumor activities against both human lung cancer cell (A549) and murine leukemia cell (P388). A1, A5, and A6 exhibited antitumor activities selectively against P388. A2 was the most efficient DNA photocleaver, which had converted supercoiled DNA from form I to form II at <1 microM. Under anaerobic conditions, the electron transfer mechanism mainly contributed to DNA photo-induced cleavage, while under aerobic conditions, superoxide anion was also involved in this process.     

Synthesis and antitumor activities of novel 5-deazaflavin-sialic acid conjugate molecules

6-Nitro-5-deazaflavin derivatives bearing O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-alpha- and beta-D-galacto-non-2-ulopyranosylonate)alkyl group (sialosylalkyl group) at N(3) or N(10) and 8-amino-5-deazaflavin substituted with the sialosylalkyl group at the amino group were synthesized and their physicochemical properties as well as antitumor effects on KB and L1210 cells have been investigated. The configurations of the glycosides were determined by 1H NMR and rate of hydrolysis of the glycosidic bond. It has been found that these conjugate molecules show significant antitumor activities. Combination of an 8-amino-5-deazaflavin with the sialosylalkyl group have been found to give rise to significant increase in antitumor activities of the compound. Antitumor effects of 6-nitro-5-deazaflavin-sialic acid conjugate molecules were similar or rather weak in comparison with those of the 6-nitro-5-deazaflavin derivatives without sialosylalkyl group.     

Novel naphthalimide–amino acid conjugates with flexible leucine moiety as side chain: Design,synthesis and potential antitumor activity

A series of novel naphthalimide derivatives with flexible leucine side chains were designed and synthesized. Their antitumor activities were evaluated against HeLa, A549, P388, HL-60, MCF-7, HCT-8 and A375 cancer cell lines in vitro. The preliminary results showed that most of the derivatives had moderate antitumor activities with the IC₅₀ values of 10^?6–10^?5 M. More importantly, compounds 8a–c exhibited exclusive antitumor activities against MCF-7 cell line. The interaction between compound 8b and BSA was also investigated. DNA binding experiments showed that these derivatives behaved as DNA intercalating agents. This work provided a novel class of naphthalimide-based lead compounds with exclusive antitumor activities against MCF-7 cell line for further optimization.     

Antitumor activities of O-sulfonated derivatives of (1-->3)-alpha-D-glucan from different Lentinus edodes

Four water-insoluble (1-->3)-alpha-D-glucans, coded L-II1, L-II2, L-II3 and L-II4, with different molecular weights were isolated from four kinds of fruiting bodies of Lentinus Edodes. The four alpha-D-glucans were O-sulfonated to obtain derivatives (SL-II) having degrees of substitution (DS) from 0.9 to 2.1 respectively. The structure of the samples was analyzed by infrared spectra, elemental analysis, and 13C NMR. The weight-average molecular weight (Mw), radii of gyration (z1/2) and intrinsic viscosity ([eta]) of the native alpha-D-glucans and O-sulfonated derivatives were measured by size-exclusion chromatography combined with laser light scattering (SEC-LLS), LLS, and viscometry in 0.2 M aqueous NaCl and in dimethyl sulfoxide (DMSO) containing 0.25 M LiCl at 25 degrees C respectively. The Mw values of the O-sulfonated derivatives were much lower than those of the native alpha-D-glucans. The experimental results indicate that the O-sulfonated derivatives are water-soluble and exist as an expanded flexible chain in aqueous solution owing to intramolecular hydrogen bonding or interaction between charge groups. The in vivo and in vitro antitumor activities of the native alpha-D-glucans and their O-sulfonated derivatives against solid tumor Sarcoma 180 cells were evaluated and compared. Interestingly, all of the O-sulfonated derivatives exhibited higher antitumor activities than those of the native glucans. The results reveal that the effect of O-sulfonation of the alpha-D-glucan on the improvement of their antitumor activities was considerable.     

Synthesis and Antitumor Activities of 5-Fluorouracil Derivatives

Abstract

1-Carbonyl 5-fluorouracil derivatives,5′-acyl-5-fluorouridines, and 5-fluorouridilic acid esters were synthesized and their antitumor activities were tested.     

Antitumor studies. part 3: design, synthesis, antitumor activity, and molecular docking study of novel 2-methylthio-, 2-amino-, and 2-(N-substituted amino)-10-alkyl-2-deoxo-5-deazaflavins

Various novel 10-alkyl-2-deoxo-2-methylthio-5-deazaflavins have been synthesized by reaction of 6-(N-alkylanilino)-2-methylthiopyrimidin-4(3H)-ones with Vilsmeier reagent. The similar 2-(N-substituted amino) derivatives were prepared by nucleophilic replacement reaction of the 2-methylthio moiety by appropriate amines. The 2-oxo derivatives (i.e., 5-deazaflavins) were obtained by acidic hydrolysis of the 2-methylthio derivatives. The antitumor activities against CCRF-HSB-2 and KB cells and the antiviral activities against HSV-1 and HSV-2 have been investigated in vitro, and many compounds showed promising antitumor activities. Furthermore, AutoDock molecular docking into PTK has been done for lead optimization of these compounds as potential PTK inhibitors. Whereas, the designed 2-deoxo-5-deazaflavins connected with amino acids at the 2-position exhibited the good binding affinities into PTK with more hydrogen bonds.     

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 biological activities of 2'-deoxy-2'-fluoro-4'-thioarabinofuranosylpyrimidine and -purine nucleosides

As part of our ongoing investigation of the synthesis of biologically interesting 2'-modified-4'-thionucleosides, we synthesized 2'-deoxy-2'-fluoro-4'-thioarabinofuranosylpyrimidine and -purine nucleosides, and evaluated their antiviral and antitumor activities. In the pyrimidine series, beta-anomers of 5-ethyluracil, 5-iodouracil, 5-chloroethyluracil, and 5-iodocytosine derivatives showed potent and selective anti-HSV-1 and HSV-2 activities in vitro. In the purine series, guanine and 2,6-diaminopurine derivatives showed prominent antiviral activities with slight cytotoxicity. On the other hand, the 5-fluorocytosine derivative (5F-4'-thioFAC) showed potent antitumor activity against both leukemia and solid tumor. Its antitumor spectrum against 14 human solid tumor and one leukemic cell lines was compared with that of 4'-thioFAC. The results showed that 5F-4'-thioFAC had an antitumor spectrum similar to that of 4'-thioFAC. However, 5F-4'-thioFAC was about 10 times less active than 4'-thioFAC.     

Synthesis and Antitumor Activity of Acyl and Benzyl Types of Prodrugs of 2′-Deoxy-2′-methylidenecytidine

Abstract

For the purpose of improvement of the in vivo antitumor activity of 2′-deoxy-2′-methylidenecytidine (DMDC, 1), we synthesized its various acyl and benzyl derivatives and evaluated them for their antitumor activity against P388 murine leukemia in mice. In terms of minimum effective dose (30% increase in life span), 5′-O-stearoyl DMDC showed two-fold higher antitumor activity than DMDC on a molar basis, when intraperitoneally (i.p.) administered to mice once a day. The antitumor activities of some other acyl derivatives were almost comparable to that of DMDC, while benzyl derivatives had no antitumor activity. Results on the hydrolysis of 5′-O-acyl derivatives by porcine liver esterase showed that at least these derivatives should not be resistant to enzymatic hydrolysis for exhibiting antitumor activity. After either an i.p. or oral dose of 3′-O-benzyl DMDC, very low concentrations of blood DMDC were seen compared with those after administration of DMDC, suggesting that the inactivity of benzyl derivatives as prodrugs was due to the minimal level of DMDC in circulation after administration.     

Novel peptide derivatives of bleomycin A5: synthesis, antitumor activity and interaction with DNA

A series of novel amino acid and peptide derivatives of bleomycin (BLM) A(5) were synthesized. All the compounds possessed significant antitumor activities in vitro against HL-60, BGC-823, PC-3MIE8, and MDA-MB-435 cell lines. Their antitumor activities against MDA-MB-435 were 10-fold higher than BLM A5. The DNA cleavage studies indicated that the hydrophobic amino acid or peptide derivatives of BLM A5 could induce higher cleavage ratio of double to single strand DNA than BLM A5. From the DNA binding studies, we found that the derivatives containing either D-conformation amino acid or basic amino acid could facilitate DNA binding of BLM.     

Synthesis, X-ray crystallographic analysis, and antitumor activity of 1-acyl-3,6-disubstituted phenyl-1,4-dihydro-1,2,4,5-tetrazines

Eleven compounds of 1-acyl-3,6-disubstituted phenyl-1,4-dihydro-1,2,4,5-tetrazines were prepared from 3,6-disubstituted phenyl-1,2-dihydro-1,2,4,5-tetrazines and anhydrides or acyl chlorines, and their structures were confirmed by single-crystal X-ray diffraction and the semi-empirical calculation of PM3 method. This reaction yields the 1,4-dihydro derivatives rather than the 1,2-dihydro derivatives. The central six-membered ring of these compounds has an obvious boat conformation and therefore is not homoaromatic. Their antitumor activities were evaluated in vitro by the SRB method for A-549 cell and the MTT method for P-388 cells. The results show that there is one compound which is highly effective against A-549 cells and two compounds which are highly effective against P-388 cells. Thus, this compound possesses potential antitumor activities and is worth researching further.     

Chemical modification and antitumor activities of two polysaccharide–protein complexes from Pleurotus tuber-regium

Two water-soluble polysaccharide-protein complexes, extracted from Pleurotus tuber-regium sclerotia, were modified chemically to obtain their sulfated and carboxymethylated derivatives. While C6 position of glucan was fully substituted, C2, C3, and C4 were only partially substituted by sulfate groups. C3, C4, and C6 position of glucan were partially substituted during the carboxymethylation. Chain conformation and antitumor activity of the native samples and their derivatives were studied. The native samples and derivatives existed in sphere conformation, and showed potent in vitro antitumor activities. Water-solubility and introduction of ionic groups played important roles in enhancing the antitumor activities of the polysaccharide–protein complexes.     

Sulfation of (1→3)-β-d-glucan from the fruiting bodies of Russula virescens and antitumor activities of the modifiers

A water-insoluble (1→3)-β-d-glucan isolated from the fresh fruiting bodies of Russula virescens was sulfated using sulfur trioxide-pyridine complex as reagent in dimethyl sulfoxide. Depending on the reaction conditions, the products showed different degrees of sulfation (DS) ranging from 0.17 to 1.17 and different weight average molecular weights (M_ws) ranging from 2.5 × 10⁴ to 1.2 × 10⁵ Da. Moreover, the antitumor activities of the five sulfated derivatives against Sarcoma 180 tumor cell were tested both in vitro and in vivo. The results indicated that the native (1→3)-β-d-glucan did not show antitumor activity, while the sulfated derivatives exhibited enhanced antitumor activities. This study demonstrated that DS and M_w could influence the antitumor activities of the sulfated derivatives.     

Antitumor studies. Part 4: Design, synthesis, antitumor activity, and molecular docking study of novel 2-substituted 2-deoxoflavin-5-oxides, 2-deoxoalloxazine-5-oxides, and their 5-deaza analogs

Various novel 10-alkyl-2-deoxo-2-methylthioflavin-5-oxides and their 2-alkylamino derivatives were prepared by facile nitrosative cyclization of 6-(N-alkylanilino)-2-methylthiopyrimidin-4(3H)-ones followed by nucleophilic replacement of the 2-methylthio moiety by different amines, and acidic hydrolysis of the 2-methylthio moiety afforded the corresponding flavin derivatives. 2-Deoxo-2-methylthio-5-deazaalloxazines and 2-deoxo-2-methylthioalloxazine-5-oxides were also prepared by Vilsmeier reaction and by nitrosation of 6-anilino-2-methylthiopyrimidin-4(3H)-ones, respectively. Then, they were subjected to nucleophilic replacement with appropriate amines to produce the corresponding 2-alkylamino derivatives. Regiospecific N(3)-alkylation of 2-deoxo-2-methylthioalloxazine-5-oxides was carried out with various alkylating agents in the usual way. The antitumor activities against CCRF-HSB-2 and KB tumor cells have been investigated in vitro, and many compounds showed promising antitumor activities. Furthermore, AutoDock molecular docking into PTK (PDB: 1t46) has been done for lead optimization of the aforementioned compounds as potential PTK inhibitors.     

Anti-invasive and anti-angiogenic activities of naturally occurring dibenzodiazepine BU-4664L and its derivatives

In the screening for antitumor leads from microbial secondary metabolites, BU-4664L (1), a naturally occurring dibenzodiazepine, was found to inhibit tumor invasion and angiogenesis in vitro. Compound 1 inhibited the gelatinase activities of MMP-2 and MMP-9 and the cellular motility. Four derivatives (2–5) were synthesized from 1 and their antitumor activities were evaluated. Compounds 3 and 4 exhibited potent anti-angiogenic effects on HUVEC, together with remarkable inhibition of cell migration at nanomolar concentrations, and showed much lower cytotoxicity.     

Synthesis of aristolactam analogues and evaluation of their antitumor activity

A series of natural aristolactams and their analogues have been prepared and evaluated for antitumor activity against human cancer cells, including multi-drug resistant cell lines. Naturally occurring aristolactams, such as aristolactam BII (cepharanone B), aristolactam BIII, aristolactam FI (piperolactam A), N-methyl piperolactam A, and sauristolactam showed moderate antitumor activities in selected cell lines. However, several synthetic aristolactam derivatives exhibited potent antitumor activities against a broad array of cancer cell lines with GI₅₀ values in the submicromolar range.