This review summarizes our work in the field of syn-thesis of natural products and their derivatives. Applica-tion of modern synthetic method is discussed in the con-text of the syntheses of both enantiomers of hydromor-phone, (–)-tetrodotoxin (a marine toxin), and selaginpul-vilins C and D (natural fluorene derivatives). Further, syn-thesis of notoincisol A, selagibenzophenones A and B is described to clarify the structural aspects of the com-pounds. Last but not least, synthesis and pharmaceutical profilation of derivatives of magnolol and honokiol is dis-cussed as well.Fulltext of this article is available on the website of this Journal.
- MeSH
- Alkynes chemical synthesis chemistry MeSH
- Biological Products MeSH
- Hydromorphone chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Lignans chemical synthesis chemistry MeSH
- Polyynes chemical synthesis chemistry MeSH
- Polycyclic Compounds chemical synthesis chemistry MeSH
- Selaginellaceae chemistry MeSH
- Chemistry Techniques, Synthetic * methods MeSH
- Tetrodotoxin chemical synthesis chemistry pharmacology MeSH
- Drug Development MeSH
- Check Tag
- Humans MeSH
Inotuzumab Ozogamicin is a CD22-directed antibody conjugated to calicheamicin, approved in adults with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (BCP-ALL). Patients aged 1-18 years, with R/R CD22 + BCP-ALL were treated at the RP2D of 1.8 mg/m2. Using a single-stage design, with an overall response rate (ORR) ≤ 30% defined as not promissing and ORR > 55% as expected, 25 patients needed to be recruited to achieve 80% power at 0.05 significance level. Thirty-two patients were enrolled, 28 were treated, 27 were evaluable for response. The estimated ORR was 81.5% (95%CI: 61.9-93.7%), and 81.8% (18/22) of the responding subjects were minimal residual disease (MRD) negative. The study met its primary endpoint. Median follow up of survivors was 16 months (IQR: 14.49-20.07). One year Event Free Survival was 36.7% (95% CI: 22.2-60.4%), and Overall Survival was 55.1% (95% CI: 39.1-77.7%). Eighteen patients received consolidation (with HSCT and/or CAR T-cells therapy). Sinusoidal obstructive syndrome (SOS) occurred in seven patients. MRD negativity seemed correlated to calicheamicin sensitivity in vitro, but not to CD22 surface expression, saturation, or internalization. InO was effective in this population. The most relevant risk was the occurrence of SOS, particularly when InO treatment was followed by HSCT.
- MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma * drug therapy MeSH
- Acute Disease MeSH
- Child MeSH
- Progression-Free Survival MeSH
- Inotuzumab Ozogamicin MeSH
- Calicheamicins * MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Child, Preschool MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Child, Preschool MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Research Support, Non-U.S. Gov't MeSH
Oplopanax elatus (Nakai) Nakai has a long history of use as an ethnomedicine by the people living in eastern Asia. However, its bioactive constituents and cancer chemopreventive mechanisms are largely unknown. The aim of this study was to prepare O. elatus extracts, fractions, and single compounds and to investigate the herb's antiproliferative effects on colon cancer cells and the involved mechanisms of action. Two polyyne compounds were isolated from O. elatus, falcarindiol and oplopandiol. Based on our HPLC analysis, falcarindiol and oplopandiol are major constituents in the dichloromethane (CH2Cl2) fraction. For the HCT-116 cell line, the dichloromethane fraction showed significant effects. Furthermore, the IC50 for falcarindiol and oplopandiol was 1.7 µM and 15.5 µM, respectively. In the mechanistic study, after treatment with 5 µg/ml for 48 h, dichloromethane fraction induced cancer cell apoptosis by 36.5% (p < 0.01% vs. control of 3.9%). Under the same treatment condition, dichloromethane fraction caused cell cycle arrest at the G2/M phase by 32.6% (p < 0.01% vs. control of 23.4%), supported by upregulation of key cell cycle regulator cyclin A to 21.6% (p < 0.01% vs. control of 8.6%). Similar trends were observed by using cell line HT-29. Data from this study filled the gap between phytochemical components and the cancer chemoprevention of O. elatus. The dichloromethane fraction is a bioactive fraction, and falcarindiol is identified as an active constituent. The mechanisms involved in cancer chemoprevention by O. elatus were apoptosis induction and G2/M cell cycle arrest mediated by a key cell cycle regulator cyclin A.
We present the application of a Glaser-Hay diyne coupling for the synthesis of conformationally constrained Nα-amino acid amides with different diyne ring sizes. Twelve-membered rings were the smallest rings that could be prepared by this approach. We observed the formation of triethylammonium adducts in the cases of smaller (10- and 11-membered) rings. Calculation of the conformational barriers for the cyclization reactions of various ring sizes demonstrated that the formation of amino acid-derived smaller rings by this reaction is thermodynamically unfavorable.
- MeSH
- Alkynes chemistry MeSH
- Amides chemical synthesis MeSH
- Amino Acids chemistry MeSH
- Amines chemistry MeSH
- Cyclization MeSH
- Diynes chemistry MeSH
- Catalysis MeSH
- Molecular Conformation MeSH
- Models, Molecular MeSH
- Solid-Phase Synthesis Techniques methods MeSH
- Thermodynamics MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
This study reports the first Co2 (CO)8 -catalyzed [2+2+2] polycyclotrimerization by the transformation of internal ethynyl groups of aromatic diyne monomers. The reaction yields polycyclotrimers of polyphenylene-type with either hyperbranched or partly crosslinked architecture. The homopolycyclotrimerization of the monomers with two ethynyl groups per one molecule, namely 1,4-bis(phenylethynyl)benzene, 4,4'-bis(phenylethynyl)biphenyl, and 4-(phenylethynyl)phenylacetylene, gives partly crosslinked, insoluble polyphenylenes. The soluble, hyperbranched polyphenylenes are generated via copolycyclotrimerization of 1,4-bis(phenylethynyl)benzene with 1,2-diphenylacetylene (average number of ethynyl groups per monomer molecule < 2). This one-step polycyclotrimerization path to hyperbranched or partly crosslinked polyphenylenes is an alternative to the synthesis of these polymers by Diels-Alder transformation of substituted cyclopentadienones. All polyphenylenes prepared exhibit photoluminescence with emission maxima ranging from 381 to 495 nm. Polyphenylenes with a less compact packing of segments are microporous (specific surface area up to 159 m2 g-1 ), which is particularly important in the case of soluble polyphenylenes because they can be potentially used to prepare microporous layers.
The chain coordination polymerization of (ethynylarene)carbaldehydes with unprotected carbaldehyde groups, namely ethynylbenzaldehydes, 1-ethynylbenzene-3,5-dicarboxaldehyde, and 3-[(4-ethynylphenyl)ethynyl]benzaldehyde, is reported for the first time. Polymerization is catalyzed with various Rh(I) catalysts and yields poly(arylacetylene)s with one or two pendant carbaldehyde groups per monomeric unit. Surprisingly, the carbaldehyde groups of the monomers do not inhibit the polymerization unlike the carbaldehyde group of unsubstituted benzaldehyde that acts as a strong inhibitor of Rh(I) catalyzed polymerization of arylacetylenes. The inhibition ability of carbaldehyde groups in (ethynylarene)carbaldehydes seems to be eliminated owing to a simultaneous presence of unsaturated ethynyl groups in (ethynylarene)carbaldehydes. The reactive carbaldehyde groups make poly[(ethynylarene)carbaldehyde]s promising for functional appreciation via various postpolymerization modifications. The introduction of photoluminescence or chirality to poly(ethynylbenzaldehyde)s via quantitative modification of their carbaldehyde groups in reaction with either photoluminescent or chiral primary amines under formation of the polymers with Schiff-base-type pendant groups is given as an example.
- MeSH
- Aldehydes chemistry MeSH
- Benzaldehydes chemistry MeSH
- Models, Chemical MeSH
- Spectrometry, Fluorescence MeSH
- Catalysis MeSH
- Molecular Structure MeSH
- Polyynes chemical synthesis chemistry MeSH
- Polymerization * MeSH
- Polymers chemical synthesis chemistry MeSH
- Proton Magnetic Resonance Spectroscopy MeSH
- Publication type
- Journal Article MeSH
Because low levels of DNA double strand breaks (DSBs) appear not to activate the ATM-mediated prophase I checkpoint in full-grown oocytes, there may exist mechanisms to protect chromosome integrity during meiotic maturation. Using live imaging we demonstrate that low levels of DSBs induced by the radiomimetic drug Neocarzinostatin (NCS) increase the incidence of chromosome fragments and lagging chromosomes but do not lead to APC/C activation and anaphase onset delay. The number of DSBs, represented by γH2AX foci, significantly decreases between prophase I and metaphase II in both control and NCS-treated oocytes. Transient treatment with NCS increases >2-fold the number of DSBs in prophase I oocytes, but less than 30% of these oocytes enter anaphase with segregation errors. MRE11, but not ATM, is essential to detect DSBs in prophase I and is involved in H2AX phosphorylation during metaphase I. Inhibiting MRE11 by mirin during meiotic maturation results in anaphase bridges and also increases the number of γH2AX foci in metaphase II. Compromised DNA integrity in mirin-treated oocytes indicates a role for MRE11 in chromosome integrity during meiotic maturation.
- MeSH
- Ataxia Telangiectasia Mutated Proteins genetics MeSH
- DNA-Binding Proteins genetics MeSH
- DNA Breaks, Double-Stranded drug effects MeSH
- DNA Repair Enzymes genetics MeSH
- Histones genetics MeSH
- Meiosis genetics MeSH
- Metaphase genetics MeSH
- Mice MeSH
- Oocytes growth & development metabolism MeSH
- DNA Damage drug effects genetics MeSH
- Zinostatin administration & dosage MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Microporous organic polymers (MOP) of a new type have been synthesised in high yields by a simple coordination polymerization of 1,3-diethynylbenzene, 1,4-diethynylbenzene and 4,4'-diethynylbiphenyl catalysed by [Rh(cod)acac] and [Rh(nbd)acac] complexes. The new MOPs are non-swellable polyacetylene-type conjugated networks consisting of ethynylaryl-substituted polyene main chains that are crosslinked by arylene linkers. Prepared MOP samples have a mole fraction of branching units (by (13)C CP/MAS NMR) from 0.30 to 0.47 and exhibit the BET (Brunaer-Emmett-Teller) surface up to 809 m(2) g(-1) and hydrogen uptake up to 0.69 wt% (77 K, H2 pressure 750 torr).
Polymer therapeutics including polymer-drug conjugates, polymer-protein conjugates and polymer-modified gene delivery vectors are addressed in this review. Brief history of the polymer therapeutics is described with a focus on the pioneering work accomplished at the Institute of Macromolecular Chemistry in Prague. The advantages of polymer therapeutics compared with lowmolecular- weight drugs are outlined. Polymer cancerostatics, polymer-protein conjugates with anti-cancer activity and polymer-modified viruses based on N-(2-hydroxypropyl) methacrylamide copolymers and biodegradable multiblock poly(ethylene glycol) polymers are chosen as examples. The current status of clinical evaluation of the polymer therapeutics is also mentioned.
- MeSH
- Biopolymers chemistry classification therapeutic use MeSH
- Cytostatic Agents MeSH
- Ethylene Glycols chemistry therapeutic use MeSH
- Financing, Organized MeSH
- Genetic Therapy methods MeSH
- Pharmaceutical Preparations MeSH
- Humans MeSH
- Maleic Anhydrides therapeutic use MeSH
- Methacrylates chemistry therapeutic use MeSH
- Polymers history chemistry therapeutic use MeSH
- Polystyrenes therapeutic use MeSH
- Zinostatin therapeutic use MeSH
- Check Tag
- Humans MeSH
Transition metal complex catalysed cocyclotrimerization of 6-alkynylpurines 1 with various diynes 2 and 6-(diynyl)purines 4 with nitriles 5 enabled to synthesize series of substituted 6-arylpurines 3 and 6-heteroarylpurines 6 in good yields. The obtained 6-aryl- and 6-heteroarylpurines were tested for cytostatic activity.
- MeSH
- Cell Line MeSH
- Cytostatic Agents chemical synthesis chemistry pharmacology MeSH
- Diynes chemistry MeSH
- Cobalt chemistry MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Nitriles chemistry MeSH
- Purines chemical synthesis chemistry pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
