Synthesis and biological evaluation of novel taxoids designed for targeted delivery to tumors

The use of drug-antibody conjugates affords a method for the targeted delivery of anticancer drugs specifically to cancer cells. Monoclonal antibodies alone usually do not possess high therapeutic efficacy, however, they are capable of targeting tumor markers selectively. We have prepared taxoids with significantly higher cytotoxicity than paclitaxel and docetaxel. These taxoids now meet the high potency required for use in a targeted-delivery approach using monoclonal antibodies. The synthesis and biological evaluation of these taxoids are reported.     

Synthesis and structure-activity relationships of new second-generation taxoids

A series of second-generation taxoids bearing a substitutent on the C-2-benzoyl group and modifications at C-3′/C-10 positions was synthesized. These taxoids exhibited 2–3 orders of magnitude higher potency than that of paclitaxel against drug-resistant human breast cancer cell lines. It is also noteworthy that three taxoids showed almost no difference in activity against drug-resistant and drug-sensitive cell lines, which are categorized as “advanced second generation taxoids“.     

Synthesis and biological evaluation of isonucleosides derived from methyl 3,5-anhydro-2-O-(2-fluorobenzyl)-D-xylofuranosides

New isonucleosides [methyl 5-(1-pyrimidinyl)furanosides] are prepared by nucleophilic opening of the oxetane ring of methyl 3,5-anhydro-2-O-(2-fluorobenzyl)-D-xylofuranoside with silylated pyrimidine bases in the presence of trimethylsilyl triflate. Structures, configurations and conformations were determined by NMR techniques and several X-ray diffraction analyses, seven of the isonucleosides were tested for cytotoxicity and activity against HIV, HSV and several other viruses.     

Synthesis and biological evaluation of new bis-indolone-N-oxides

A series of bis-indolone-N-oxides, 1a–f, was prepared from bis(ethynyl)benzenes and o-halonitroaryls and studied for their in vitro antiplasmodial activities against Plasmodium falciparum and representative strains of bacteria and candida as well as for their cytotoxicity against a human tumor cell line (MCF7). They did not cause any haemolysis (300 μg mL⁻¹). Of the synthesized bis-indolones, compound 1a had the most potent antiplasmodial activity (IC₅₀ = 0.763 μmol L⁻¹ on the FcB1 strain) with a selectivity index (CC₅₀ MCF7/IC₅₀ FcB1) of 35.6. No potency against the tested microbial strains was observed.     

Synthesis and biological evaluation of methoxylated analogs of the newer generation taxoids IDN5109 and IDN5390

Starting from 10-deacetylbaccatin III (7), the 2-debenzoyl-2-m-methoxybenzoyl analogs of the newer generation taxoids IDN5109 (3) and IDN5390 (4) were synthesized. The biological evaluation of these compounds (5 and 6, respectively) showed a general increase of cytotoxicity, as observed in first-generation anticancer taxanes.     

Synthesis and evaluation of cytotoxic activities of new guanidines derived from carbazoles

Several new alkylguanidines derived from carbazole have been synthesized in a simple one-pot reaction starting from 3-aminocarbazole derivatives. The aminocarbazoles were reacted with ethoxycarbonylisothiocyanate, to give thiourea intermediates, followed by the addition of an alkylamine and HgCl₂ to give ethoxycarbonylguanidine intermediates. The reaction mixture was then heated at 160 °C to give the N-(1,4-dimethyl-9H-carbazol-3-yl)-N′-alkylguanidines.The cytotoxic activity of all the synthesized guanidines was evaluated against different cell lines.     

Synthesis and biological activity evaluation of lignan lactones derived from (-)-cubebin

The anti-inflammatory and analgesic effects of three dibenzylbutyrolactone lignans, (-)-hinokinin (2), (-)-6,6'-dinitrohinokinin (3), and (-)-6,6'-diaminohinokinin (4), obtained by partial synthesis from (-)-cubebin (1), were investigated using different animal models. It was observed that compounds (1) and (2) inhibited the edema formation in the rat paw edema assay at the same level and that all responses were dose dependent. Also, at the dose of 30 mg/kg, compounds 1, 2, 3, and 4 inhibited the edema formation by 53%, 63%, 54%, and 82%, respectively, at the third hour of the experiment. In the acetic acid-induced writhing test in mice, compounds 2 and 4 produced inhibition levels of 97% and 92%, respectively, while 3 displayed lower effect (75%), which was still higher than 1. The assayed compounds neither displayed activity in the cell migration test nor in the hot plate test.     

Two new taxoids from Taxus chinensis

Two new taxoids, 2,20-O-diacetyltaxumairol N (1) and 14beta-hydroxy-10-deacetyl-2-O-debenzoylbacatin III (2), were isolated from the needles and stems of Taxus chinensis. Their structures were determined on the basis of extensive 1D- and 2D-NMR-spectral analysis. Compound 1 showed weak cytotoxicity activity against T-24 (IC50 = 34 microg/ml) and QGY-7701 (IC50 = 22 microg/ml) cancer lines. Compound 2 showed no obvious cytotoxicity activity against T-24 (IC50 > 100 microg/ml) and QGY-7701 (IC50 > 100 microg/ml) cancer lines.     

Synthesis and biological evaluation of novel piperidine carboxamide derived calpain inhibitors

Calpain inhibitors which are derived from piperidine carboxamides in the P2 region were prepared and evaluated for mu-calpain inhibition. In particular, the keto amides 11f and 11j have Ki of 30 and 9 nM and display a more than 100-fold selectivity over the closely related cysteine protease cathepsin B. Furthermore, these compounds inhibit NMDA induced convulsions in mice indicating that calpain inhibition in brain results in some anticonvulsive properties.     

Synthesis and biological evaluation of 2-quinolineacrylamides

A series of C6-substituted N-hydroxy-2-quinolineacrylamides (3–15), with four types of bridging groups have been synthesized. Most of these compounds exhibit antiproliferative activity against A549 and HCT116 cells and Western blot analysis revealed that they are able to inhibit HDAC. Measurement of the HDAC isoform activity of ether-containing compounds showed that compound 9 has distinct HDAC6 selectivity, more than 300-fold over other isoforms. This paper describes the development of 6-aryloxy-N-hydroxy-2-quinolineacrylamides as potential HDAC6 inhibitors.     

Synthesis and biological evaluation of new derivatives of emodin

Drugs containing an anthraquinone moiety such as daunorubicin (Daunoblastin) and mitoxantrone (Onkotrone) constitute some of the most powerful cytostatics. They suppress tumor growth mainly by intercalation into DNA and inhibition of topoisomerase II, and are suspected to generate free radicals leading to DNA strand scission. We established a novel strategy for obtaining new highly functionalized derivatives of emodin (1,3,8-trihydroxy-6-methyl-anthraquinone). Using emodin, DIB, and an appropriate amine as starting materials, we obtained a wide range of emodin-related structures by one-pot synthesis. Several of these derivatives showed stronger cytotoxic and cytostatic activity than emodin. In particular, compound 6 was highly effective on the HepG2 tumor cell line, but did not show any cytotoxicity on normal hepatocytes. In addition to this favorable feature, compound 6 revealed interesting binding properties to a recombinant fragment of the multi-drug-resistance transporter, pgp, and reversed the multi-drug-resistance phenotype of H4-II-E cells, thus making this compound a promising potential anti-tumor drug.     

Synthesis and biological evaluation of a new vitamin D(2) analogue

A new vitamin D(2) analogue was synthesized using the Julia-Kocienski olefination. It has antiproliferative effects on cell lines from squamous cell carcinomas of colon and head and neck, but is also as hypercalcaemic as calcitriol in vivo.     

Synthesis and biological evaluation of new 4-thiazolidinone derivatives

A series of new 2-aryl-4-thiazolidinones (3 and 4) was synthesized from 2-hydroxy-2,2-diphenyl-N’-[(substituted phenyl)methylene]acetohydrazides (2) and mercaptoacetic acid or 2-mercaptopropionic acid. The antimycobacterial activity of these compounds was determined and several leads with 95–99% inhibition at 6.25 μg/mL test concentration were identified. In addition, antitumor activities were measured against several tumor cell lines, and significant growth inhibition was observed for compound 4p. Taken together, 2-aryl-4-thiazolidinones were shown to be promising scaffolds for both antimycobacterial and tumor-targeting compounds.     

Synthesis and biological evaluation of some new pyridazinone derivatives

A series of pyridazinone derivatives (19-34) were synthesized with an aim to synthesize safer anti-inflammatory agents. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation (LPO) actions. The percentage inhibition in edema at different time intervals indicated that compounds 20, 26, 28 and 34 exhibited good anti-inflammatory potential, comparable with that of ibuprofen (85.77%) within a range of 67.48-77.23%. The results illustrate that 5-(4-fluoro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone (26) and 5-(4-chloro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone (20) showed best anti-inflammatory activity. Furthermore, activity is more in case of chloro substitution as compared with methyl-substitution. The compounds synthesized were also evaluated for their ulcerogenic and LPO action and showed superior gastrointestinal safety profile along with reduction in LPO as compared with that of the ibuprofen.     

Synthesis and biological evaluation of some new pyridazinone derivatives

A series of pyridazinone derivatives (19–34) were synthesized with an aim to synthesize safer anti-inflammatory agents. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation (LPO) actions. The percentage inhibition in edema at different time intervals indicated that compounds 20, 26, 28 and 34 exhibited good anti-inflammatory potential, comparable with that of ibuprofen (85.77%) within a range of 67.48–77.23%. The results illustrate that 5-(4-fluoro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone (26) and 5-(4-chloro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone (20) showed best anti-inflammatory activity. Furthermore, activity is more in case of chloro substitution as compared with methyl-substitution. The compounds synthesized were also evaluated for their ulcerogenic and LPO action and showed superior gastrointestinal safety profile along with reduction in LPO as compared with that of the ibuprofen.     

Synthesis and evaluation of potential affinity labels derived from endomorphin-2.

In an attempt to identify potential peptide-based affinity labels for opioid receptors, endomorphin-2 (Tyr-Pro-Phe-PheNH2), a potent and selective endogenous ligand for mu-opioid receptors, was chosen as the parent peptide for modification. The tetrapeptide analogs were prepared using standard Fmoc-solid phase peptide synthesis in conjunction with incorporation of Fmoc-Phe(p-NHAlloc) and modification of the p-amino group. The electrophilic groups isothiocyanate and bromoacetamide were introduced into the para position on either Phe3 or Phe4; the corresponding free amine-containing peptides were also prepared for comparison. The peptides bearing an affinity label group and their free amine analogs were evaluated in a radioligand-binding assay using Chinese hamster ovary (CHO) cells expressing mu- and delta-opioid receptors. Modification on Phe4 was better tolerated than on Phe3 for mu-receptor binding. Among the analogs tested, [Phe(p-NH2)4]endomorphin-2 showed the highest affinity (IC50 = 37 nm) for mu-receptors. The Phe(p-NHCOCH2Br)4 analog displayed the highest mu-receptor affinity (IC50 = 158 nm) among the peptides containing an affinity label group. Most of the compounds exhibited negligible binding affinity for delta-receptors, similar to the parent peptide.     

Potent inhibitors of CDK5 derived from roscovitine: Synthesis,biological evaluation and molecular modelling

Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer’s or Parkinson’s diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC₅₀ = 350 nM; CDK5/p25, IC₅₀ = 200 nM). These new molecules were synthesized using an original Buchwald–Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC₅₀ values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC₅₀ values ranging from 2 to 9 μM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC₅₀ values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer’s disease (3g, 3h, 4m; IC₅₀ values ranging from 300 to 400 nM).     

Synthesis and biological evaluation of 2-thiopyrimidine derivatives

Various 2-thiopyrimidine derivatives have been synthesized by an efficient, one-pot reaction of functionalized amines with either 4-isothiocyanato-4-methyl-2-pentanone or 3-isothiocyanatobutanal. All the synthesized compounds were fully characterized by elemental analysis (CHN), FT-IR, (1)H NMR, and mass spectral data. One of the compounds, 7,7,8a-trimethyl-hexahydro-thiazolo[3,2-c]pyrimidine-5-thione (17) showed good anti-inflammatory (37.4% at 100 mg/kg p.o.) and analgesic activity (75% at 100 mg/kg p.o.). 7-(1-Mercapto-3,3,4a-trimethyl-4,4a,5,9b-tetrahydro-3H-pyrido[4,3-b]indol-7-yl)-3,3,4a-trimethyl-3,4,4a,5-tetrahydro-benzo[4,5]imidazo[1,2-c]pyrimidine-1-thiol (3) showed moderate activity against CDK-1 (IC(50)=5 microM). The other compounds showed moderate anti-inflammatory (5-20%), analgesic (25-75%) and protein kinase (CDK-5, GSK-3) inhibitory activities (IC(50)> 10 microM).     

Synthesis and in silico biological activity evaluation of new N-substituted pyrazolo-oxazin-2-one systems

Cyclisation of pyrazolo-beta-enaminones 3 readily obtained from 4-aceto acetyl pyrazol 2 with triphosgene led to the formation of N-substituted pyrazolo-1,3-oxazin-2-ones 4 in good yields. Estimation of pharmacotherapeutic potential, possible molecule mechanisms of action, toxic/side effects and interaction with drug-metabolizing enzymes were made for synthesised compounds on the basis of prediction of activity spectra for substances (PASS) prediction results and their analysis by PharmaExpert software. COX inhibition predicted by PASS was confirmed by experimental evaluation.     

Synthesis and biological evaluation of new spin-labeled derivatives of podophyllotoxin

In order to find compounds with superior bioactivity and less toxicity, a series of spin-labeled podophyllotoxin derivatives were synthesized and tested for the partition coefficients and cytotoxicity against P-388 and A-549. Furthermore, we also determined antioxidant activities of target molecular in tissues of SD rats by the TBA method. Results revealed that most synthesized compounds showed more significant cytotoxicity against P-388 and A-549 in vitro than VP-16. Among them, 9d exhibited most potent cytotoxicity against P-388 and A-549 cells (IC50 is <0.01 and 0.13 microM, respectively). Also, the antioxidative activities showed that the modified compounds of 4'-demethylepipodophyllotoxin (9a-d and 10a-c) are higher than those of podophyllotoxin series (8a-d). The relationship between the cytotoxicity and antioxidative activity discussed.