Original Vinca Derivatives: From P‑Glycoprotein Substrates to P‑Glycoprotein Inhibitors

The first example of vinca derivatives <b>16</b>–<b>18</b> able to modulate P-glycoprotein (Pgp) efflux activity is reported. They were elaborated in two steps from vinorelbine <b>3</b> (VLN) by a modification of the velbenamine moiety. These compounds were able to decrease efficiently Pgp mediated influx and efflux of rhodamine-123 (Rho) and to restore the cytotoxicity of vinorelbine <b>3</b> (VLN) and doxorubicin (Dox) on K562R (dox-resistant) cell lines

Original Vinca Derivatives: From P‑Glycoprotein Substrates to P‑Glycoprotein Inhibitors

The first example of vinca derivatives <b>16</b>–<b>18</b> able to modulate P-glycoprotein (Pgp) efflux activity is reported. They were elaborated in two steps from vinorelbine <b>3</b> (VLN) by a modification of the velbenamine moiety. These compounds were able to decrease efficiently Pgp mediated influx and efflux of rhodamine-123 (Rho) and to restore the cytotoxicity of vinorelbine <b>3</b> (VLN) and doxorubicin (Dox) on K562R (dox-resistant) cell lines

Palladium-Catalyzed One-Pot Reaction of Hydrazones, Dihaloarenes, and Organoboron Reagents: Synthesis and Cytotoxic Activity of 1,1-Diarylethylene Derivatives

A new three-component assembly reaction between <i>N</i>-tosylhydrazones, dihalogenated arenes, and boronic acids or boronate esters was developed, producing highly substituted 1,1-diarylethylenes in good yields. The two C–C bonds formed through this coupling have been catalyzed by a single Pd-catalyst in a one-pot fashion. It is noted that the one-pot pinacol boronate cross-coupling reaction generally provides products in high yields, offers an expansive substrate scope, and can address a broad range of aryl, styrene, vinyl, and heterocyclic olefinic targets. The scope of this one-pot coupling has been also extended to the synthesis of the 1,1-diarylethylene skeleton of the natural product ratanhine. The new compounds were evaluated for their cytotoxic activity, and this allowed the identification of compound <b>4ab</b> that exhibits excellent antiproliferative activity in the nanomolar concentration range against HCT116 cancer cell lines

Reduction-Responsive Cholesterol-Based Block Copolymer Vesicles for Drug Delivery

We developed a new robust reduction-responsive polymersome based on the amphiphilic block copolymer PEG-SS-PAChol. The stability and robustness were achieved by the smectic physical cross-linking of cholesterol-containing liquid crystal polymer PAChol in the hydrophobic layer. The reduction-sensitivity was introduced by the disulfide bridge (-S–S-) that links the hydrophilic PEG block and the hydrophobic PAChol block. We used a versatile synthetic strategy based on atom transfer radical polymerization (ATRP) to synthesize the reduction-responsive amphiphilic block copolymers. The reductive cleavage of the disulfide bridge in the block copolymers was first evidenced in organic solution. The partial destruction of PEG-SS-PAChol polymersomes in the presence of a reducing agent was then demonstrated by cryo-electron microscopy. Finally, the calcein release from PEG-SS-PAChol polymersomes triggered by glutathione (GSH) was observed both in PBS suspension and in vitro inside the macrophage cells. High GSH concentrations (≥35 mM in PBS or artificially enhanced in macrophage cells by GSH-OEt pretreatment) and long incubation time (in the order of hours) were, however, necessary to get significant calcein release. These polymersomes could be used as drug carriers with very long circulation profiles and slow release kinetics

Synthesis of a 3‑(α-Styryl)benzo[<i>b</i>]‑thiophene Library via Bromocyclization of Alkynes and Palladium-Catalyzed Tosylhydrazones Cross-Couplings: Evaluation as Antitubulin Agents

A library of functionalized 3-(α-styryl)-benzo­[<i>b</i>]­thiophenes, endowed with a high level of molecular diversity, was efficiently synthesized by applying a synthetic sequence that allowed introduction of various substituents on aromatic A, B, and C-rings. The strategy developed involves the synthesis of 3-bromobenzo­[<i>b</i>]­thiophene derivatives through a bromocyclization step of methylthio-containing alkynes using <i>N</i>-methylpyrrolidin-2-one hydrotribromide reagent (MPHT). Further coupling of 3-bromobenzothiophenes under palladium-catalysis with <i>N</i>-tosylhydrazones efficiently furnished 2-aryl-3-(α-styryl)­benzo­[<i>b</i>]­thiophene derivatives. The antiproliferative properties of target compounds were studied. Among them, compound <b>5m</b> has demonstrated submicromolar cytotoxic activity against HCT-116 cell line, and inhibited the polymerization of tubulin at micromolar level comparable to that of CA-4

One-Pot Synthesis of Vinca Alkaloids–Phomopsin Hybrids

Hybrids of vinca alkaloids and phomopsin A have been elaborated with the aim of interfering with the “vinca site” and the “peptide site” of the vinca domain in tubulin. They were synthesized by an efficient one-pot procedure that directly links the octahydrophomopsin lateral chain to the velbenamine moiety of 7′-<i>homo</i>-anhydrovinblastine. In their modeled complexes with tubulin, these hybrids were found to superimpose nicely on the tubulin-bound structures of vinblastine and phomopsin A. This good matching can account for the fact that two of them are very potent inhibitors of microtubules assembly and are cytotoxic against four cancer cell lines

A New Series of Succinimido-ferrociphenols and Related Heterocyclic Species Induce Strong Antiproliferative Effects, Especially against Ovarian Cancer Cells Resistant to Cisplatin

Ferrociphenols are known to display anticancer properties by original mechanisms dependent on redox properties and generation of active metabolites such as quinone methides. Recent studies have highlighted the positive impact of oxidative stress on chemosensitivity and prognosis of ovarian cancer patients. Ovarian adenocarcinomas are shown to be an excellent model for defining the impact of selected ferrociphenols as new therapeutic drugs for such cancers. This work describes the syntheses and preliminary mechanistic research of unprecedented multitargeting heterocyclic ferrociphenols bearing either a succinimidyl or phthalimidyl group that show exceptional antiproliferative behavior against epithelial ovarian cancer cells resistant to cisplatin. Owing to the failure of the present pharmaceutical options, such as carboplatin a metallodrug based on Pt coordination chemistry, these species may help to overcome the problem of lethal resistance. Currently, ferrociphenolic entities generally operate via apoptotic and senescence pathways. We present here our first results in this new cyclic-imide series

Synthesis and Biological Evaluation of a New Series of Highly Functionalized 7′-<i>homo</i>-Anhydrovinblastine Derivatives

Sixteen new 7′-<i>homo</i>-anhydrovinblastine derivatives were prepared in one or two steps from vinorelbine by means of an original and regiospecific rearrangement and subsequent diastereoselective reduction. This strategy has allowed fast access to a family of vinca alkaloid derivatives with an enlarged and functionalized ring C′. Their synthesis and biological evaluation are reported. One compound (compound <b>35</b>) is 1.7 times more active than vinorelbine as a tubulin assembly inhibitor. Moreover, some of these compounds are highly cytotoxic, and two of them are more potent than vinorelbine on HCT116 and K562 cell lines. Molecular modeling studies, carried out with two of the new vinca derivatives, provide useful hints about how a given functionalization introduced at positions 7′ and 8′ of the C′ ring results in improved binding interactions between one of the new derivatives and the interdimer interface when compared to the parent compound vinblastine

Antibacterial Labdane Diterpenoids from Vitex vestita

A large-scale in vitro screening of tropical plants using an antibacterial assay permitted the selection of several species with significant antibacterial activities. Bioassay-guided purification of the dichloromethane extract of the leaves of the Malaysian species Vitex vestita, led to the isolation of six new labdane-type diterpenoids, namely, 12-epivitexolide A (<b>2</b>), vitexolides B and C (<b>3</b> and <b>4</b>), vitexolide E (<b>8</b>), and vitexolins A and B (<b>5</b> and <b>6</b>), along with six known compounds, vitexolides A (<b>1</b>) and D (<b>7</b>), acuminolide (<b>9</b>), 3β-hydroxyanticopalic acid (<b>10</b>), 8α-hydroxyanticopalic acid (<b>11</b>), and 6α-hydroxyanticopalic acid (<b>12</b>). Their structures were elucidated on the basis of 1D and 2D NMR analyses and HRMS experiments. Both variable-temperature NMR spectroscopic studies and chemical modifications were performed to investigate the dynamic epimerization of the γ-hydroxybutenolide moiety of compounds <b>1</b>–<b>4</b>. Compounds were assayed against a panel of 46 Gram-positive strains. Vitexolide A (<b>1</b>) exhibited the most potent antibacterial activity with minimal inhibitory concentration values ranging from 6 to 96 μM, whereas compounds <b>2</b> and <b>6</b>–<b>9</b> showed moderate antibacterial activity. The presence of a β-hydroxyalkyl-γ-hydroxybutenolide subunit contributed significantly to antibacterial activity. Compounds <b>1</b>–<b>4</b> and <b>6</b>–<b>9</b> showed cytotoxic activities against the HCT-116 cancer cell line (1 < IC₅₀<i>s</i> < 10 μM) and human fetal lung fibroblast MRC5 cell line (1 < IC₅₀<i>s</i> < 10 μM for compounds <b>1</b>,<b> 2</b>,<b> 7</b>,<b> 8</b>, and <b>9</b>)

Cytotoxic Prenylated Stilbenes Isolated from <i>Macaranga tanarius</i>

With the aim of discovering new cytotoxic prenylated stilbenes of the schweinfurthin series, <i>Macaranga tanarius</i> was selected for detailed phytochemical investigation among 21 <i>Macaranga</i> species examined by using a molecular networking approach. From an ethanol extract of the fruits, seven new prenylated stilbenes, schweinfurthins K–Q (<b>7</b>–<b>13</b>), were isolated, along with vedelianin (<b>1</b>), schwenfurthins E–G (<b>2</b>–<b>4</b>), mappain (<b>5</b>), and methyl-mappain (<b>6</b>). The structures of the new compounds were established by spectroscopic data analysis. The relative configurations of compounds <b>8</b>, <b>12</b>, and <b>13</b> were determined based on ROESY NMR spectroscopic analysis. The cytotoxic activities of compounds <b>1</b>–<b>13</b> were evaluated against the human glioblastoma (U87) and lung (A549) cancer cell lines