Probing the Anticancer Mechanism of (−)‐Ainsliatrimer A through Diverted Total Synthesis and Bioorthogonal Ligation

Herein, we report an efficient approach for exploring the novel anticancer mechanism of (?)‐ainsliatrimer A, a structurally complex and unique trimeric sesquiterpenoid, through a combined strategy of diverted total synthesis (DTS) and bioorthogonal ligation (TQ ligation), which allowed us to visualize the subcellular localization of this natural product in live cells. Further biochemical studies facilitated by pretarget imaging revealed that PPARγ, a nucleus receptor, was a functional cellular target of ainsliatrimer A. We also confirmed that the anticancer activity of ainsliatrimer A was caused by the activation of PPARγ.     

Ferrocenyl Quinone Methide–Thiol Adducts as New Antiproliferative Agents: Synthesis,Metabolic Formation from Ferrociphenols,and Oxidative Transformation

Ferrociphenols ( FCs ) and their oxidized, electrophilic quinone methide metabolites ( FC‐QMs ) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC‐QMs toward cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FC‐SR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of the FC‐SR adducts exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either revert to their FC‐QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC‐SR‐QM . These results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs , and also open the way to a new series of organometallic antitumor compounds.     

Synthetic prodiginine obatoclax (GX15-070) and related analogues: anion binding, transmembrane transport, and cytotoxicity properties

Synthetic prodiginine obatoclax shows promise as a potential anticancer drug. This compound promotes apoptosis of cancer cells, although the mechanism of action is unclear. To date, only the inhibition of BCL-2 proteins has been proposed as a mechanism of action. To gain insight into other possible modes of action, we have studied the anion-binding properties of obatoclax and related analogues in solution, in the solid state, and by means of density functional theory calculations. These compounds are well suited to interact with anions such as chloride and bicarbonate. The anion-transport properties of the compounds synthesized were assayed in model phospholipid liposomes by using a chloride-selective-electrode technique and (13)C NMR spectroscopy. The results demonstrated that these compounds are efficient anion exchangers that promote chloride, bicarbonate, and nitrate transport through lipid bilayers at very low concentrations. In vitro studies on small-cell lung carcinoma cell line GLC4 showed that active ionophores are able to discharge pH gradients in living cells and the cytotoxicity of these compounds correlates well with ionophoric activity.     

Design and synthesis of angucyclinone AB-pyrido[2,3-d] pyrimidine analogues

The preparation of two pyrimido[4,5-c]isoquinoline-7,10-quinones from acylhydroquinones and 1,3-dimethyl-5-aminouracil and their cycloadditions with 1-trimethylsilyloxybutadiene and 1-dimethylamino-3-methyl-1-azabutadiene is described. The remarkable regiocontrol of these cycloadditions that yield stable 1:1 cycloadducts is discussed on the basis of steric interactions into the pyrimido[4,5-c]isoquinoline-7,10-quinones. The access to angucyclinone AB-pyridopyrimidine analogues from Diels-Alder adducts and preliminar evidences on their antitumour activities are also reported.     

Study of Michael addition on chalcones and or chalcone analogues

Michael addition reaction of 1,3-diphenyl-propenone 1a, e, and f with o-amino thiophenol in the presence of indium trichloride gave the benzothiazine derivatives 2a–c. Condensation of the compound 1a, e with o-phenylene diamine in triethylamine gave the benzodiazepine derivatives 3a–b. Cyclization of 1d with malononitrile in the presence of NaOR/EtOH gave the compound 4. Addition of thiobarbituric acid in triethylamin to 1a gave 5. Condensation of compound 1c with malononitrile in the presence ammonium acetate gave compound 6. 1,3-diphenyl-propenone 1a used as key starting chalcone to react with different active methylene reagents under phase-transfer catalysis condition gave compound 7–9. The structures of the prepared compounds were mainly confirmed on the basis of spectroscopic methods.     

Cross-linked Polyamides Prepared through Direct Bulk Michael Addition and Polycondensation from 1,6-Hexanediamine and Methyl Acrylate

Cross-linked polyamides(c PAs)were prepared through direct bulk Michael addition and subsequent polycondensation.Several mixed hexanediamine multi-esters(HDAMEs)were generated through the Michael addition of 1,6-hexanediamine(HDA)and methyl acrylate(MA)at50℃ with different HDA/MA molar ratios.Melt polycondensation of HDAMEs then proceeded at 150 or 170℃ in flasks to obtain viscous fluids,and curing was continued in tetrafluoroethylene molds to obtain c PA films.The Michael addition was monitored on the basis of FTIR and ESI-MS spectra.The c PA films were characterized by DSC,TGA,dynamic mechanical analysis,and tensile test.These directly prepared c PAs exhibited Tg of 1–39℃,tensile strength of up to 45 MPa,and strain at break from 18%to 40%.The c PAs with high tensile strength and good toughness were successfully synthesized through the direct bulk Michael addition from HDA and MA followed with polycondensation.     

A sequential reaction process to assemble polysubstituted indolizidines, quinolizidines and quinolizidine analogues

The ω-iodo-α,β-alkynoates and their ketone, sulfone or phosphonate analogues react with δ-chloropropylamines in MeCN assisted with K₂CO₃ to undergo a sequential S_N2/Michael addition/S_N2/S_N2 reaction process, giving polysubstituted indolizidines or quinolizidines in good to excellent yields. This sequential reaction process is also compatible with three other substituted α,β-alkynoates, affording quinolizidine analogues in moderate to good yields.     

On-Resin Preparation of Allenamidyl Peptides: A Versatile Chemoselective Conjugation and Intramolecular Cyclisation Tool

The ability to modify peptides and proteins chemoselectively is of continued interest in medicinal chemistry, with peptide conjugation, lipidation, stapling, and disulfide engineering at the forefront of modern peptide chemistry. Herein we report a robust method for the on-resin preparation of allenamide-modified peptides, an unexplored functionality for peptides that provides a versatile chemical tool for chemoselective inter- or intramolecular bridging reactions with thiols. The bridging reaction is biocompatible, occurring spontaneously at pH 7.4 in catalyst-free aqueous media. By this “click” approach, a model peptide was successfully modified with a diverse range of alkyl and aryl thiols. Furthermore, this technique was demonstrated as a valuable tool to induce spontaneous intramolecular cyclisation by preparation of an oxytocin analogue, in which the native disulfide bridge was replaced with a vinyl sulfide moiety formed by thia-Michael addition of a cysteine thiol to the allenamide handle.