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Starting from two commercially available phenol derivatives, the thyroid hormone analog, GC-1, was successfully prepared. The strategy featured a convergent coupling of the two halves via the Lewis/Brønsted acid-mediated regioselective Friedel-Crafts-type (FC-type) benzylation to furnish the corresponding diarylmethane core as the key step. Various transition metal triflates were screened as catalysts for this key step, among which Bi(OTf)3 was found to be the most effective. [ABSTRACT FROM AUTHOR]

As a promising class of bioactive marine pyrrole alkaloids, lamellarins reportedly act on multiple targets to suppress the vitality of various cancer cell lines. Nevertheless, an in-depth understanding of the molecular mechanisms governing their cytotoxicity is still in demand. Here we report that while activating intrinsic apoptosis, up to 5 μM of lamellarins and their lactam-containing analogs, azalamellarins, also induced mitochondrial stress responses and autophagy in HeLa cervical cancer cells. Detailed characterization of the mitochondria in the treated cells revealed shifted abundance of the two optic atrophy protein 1 (Opa1) isoforms, disturbed morphology, and dissipated membrane potential, leading to PTEN-induced kinase-1 (PINK1) and microtubule-associated protein 1 light chain 3-II (LC3-II) accumulation as a molecular signature of mitophagy. Furthermore, an acute treatment with lamellarins also modulated cellular autophagy flux as evidenced by elevated LC3-II levels, LC3 puncta formation, and p62 degradation. Surprisingly, clustered regularly interspaced short palindromic repeats (CRISPR)-based suppression of autophagy transiently affected the number of apoptotic cells induced by these compounds. Our findings illustrate the potential of these alkaloids for further development into prospective anti-cancer agents. [ABSTRACT FROM AUTHOR]

Eleven novel clerodane-type diterpenoids, grewiifopenes A-K (1-4 and 12-18), along with nine known compounds (5-11, 19, and 20) were purified from the dichloromethane extract of the twigs and stems of Casearia grewiifolia Vent. (Salicaceae). Their spectroscopic data, including the NMR, HRESIMS, and electronic circular dichroism calculations were employed to completely characterize and elucidate the chemical structures and absolute configurations. The clerodane diterpenoids possessing a 6-OH group and no substitution at C-7 exhibited greater cytotoxic activity than others, with their IC 50 values ranging from 0.3 to 2.9 μM. Isocaseamembrin E (7) exhibited antibacterial activity against Staphylococcus aureus, while isocaseamembrin E (7), corymbulosin X (8), caseargrewiin A (9), kurzipene A (10), and balanspene F (11) exhibited antibacterial activity against Bacillus cereus., (© 2024. The Author(s).)

Analogs of pyrrole alkaloid lamellarins exhibit anticancer activity by modulating multiple cellular events. Lethal doses of several lamellarins were found to enhance autophagy flux in HeLa cells, suggesting that lamellarins may modulate protein homeostasis through the interference of proteins or kinases controlling energy and nutrient metabolism. To further delineate molecular mechanisms and their targets, our results herein show that azalamellarin D (AzaD) cytotoxicity could cause translational attenuation, as indicated by a change in eIF2α phosphorylation. Intriguingly, acute AzaD treatment promoted the phosphorylation of GCN2, a kinase that transduces the integrated stress response (ISR), and prolonged exposure to AzaD could increase the levels of the phosphorylated forms of eIF2α and the other ISR kinase protein kinase R (PKR). However, the effects of AzaD on ISR signalling were marginally abrogated in cells with genetic deletion of GCN2 and PKR, and evaluation of protein target engagement by cellular thermal shift assay (CETSA) revealed no significant interaction between AzaD and ISR kinases. Further investigation revealed that acute AzaD treatment negatively affected mechanistic target of rapamycin (mTOR) phosphorylation and signalling. The analyses by CETSA and computational modelling indicated that mTOR may be a possible protein target for AzaD. These findings indicate the potential for developing lamellarins as novel agents for cancer treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Nazarov cyclization of the ( E )-(2-stilbenyl)methanols under the catalysis of p -TsOH immobilized on silica (PTS-Si) proceeded to give the corresponding indanyl cation with the exclusive trans relationship at the two newly formed adjacent stereogenic centers. The ensuing intramolecular nucleophilic addition by the MOM-protected phenol ( m = 0) or benzyl alcohol ( m = 1) furnished the Indane-fused benzofuran [5/5] or isochroman [5/6] system, respectively, with the exclusive cis stereocontrol at the two-carbon ring junction. Thus, in a single step, from nonchiral starting materials, the intramolecular cascade carbocation cyclization (CCC) furnished the [5/5] or [5/6] oxygen-containing Indane fused-ring systems in moderate to good yields with excellent stereoselectivity on all three contiguous stereogenic centers.

Dulcisenes C-E, undescribed polyoxygenated cyclohexenes and twenty-one known compounds were isolated from the dichloromethane extract of the leaves of Uvaria dulcis Dunal. The structures of these undescribed compounds were determined by spectroscopic data analyses, including 1D and 2D NMR, IR, and MS techniques; their absolute configurations were analyzed by NOESY and ECD spectra. Cytotoxicity of sixteen more abundant isolates was evaluated. Cherrevenone and 2',3'-dihydroxy-4',6'-dimethoxychalcone exhibited cytotoxic activity against some cancer cell lines with IC 50 values in the range of 3.3-11.8 μM., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Seven previously undescribed acridones, named atalantiaphyllines A-G, along with twenty-six known compounds were isolated from the dichloromethane extracts of roots and stems of Atalantia monophylla DC. Their structures were elucidated by analysis of extensive NMR and HRMS data. Aromatase inhibition, cytotoxicity against MOLT-3, HepG2, A549 and HuCCA-1 cell lines and DPPH radical scavenging activity of these compounds were evaluated. Most of the tested acridones exhibited higher potency in inhibiting aromatase than the positive control, ketoconazole, with IC 50 values in the range of 0.08-2.0 μM. In the cytotoxicity assay, cycloataphylline A, N-methylbuxifoliadine E and atalantiaphylline G were selectively cytotoxic against MOLT-3 cell line with IC 50 values of 8.0, 5.4 and 9.8 μM, respectively, while only atalaphyllidine exhibited highest antioxidant activity as evaluated by DPPH free radical scavenging assay with an IC 50 value of 22.4 μM., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In four steps from the tricyclic core, palodesangren B trimethyl ether and palodesangren D dimethyl ether could be synthesized in 29 and 18% overall yields, respectively. A reaction sequence comprising the regioselective MgCl 2 -mediated Casnati-Skattebøl ortho -formylation of phenol, Wittig methylenation, acryloylation, and Ru(II)-catalyzed ring-closing metathesis (RCM) led to the formation of the final 2 H -pyran-2-one ring of the desired tetracyclic core.

The diene methyl ethers or acetates, constructed from the Li-Br exchange/addition reactions of 2-vinylbenzaldehydes and 2-(but-3-en-1-yl)bromoarenes followed by etherification or acetylation of the corresponding alcohols, smoothly underwent the ring-closing metathesis (RCM) by using Hoveyda-Grubbs II as a catalyst to provide the corresponding benzannulated ( Z)-cyclononenes as single products in good yields (up to 75%). The ensuing one-pot acid-mediated transannular cyclization/nucleophilic addition at C7 furnished the corresponding tetrahydro-5 H-benzo[ c]fluorenes as single stereoisomers with the exclusive cis stereochemistry at the ring junction (C5-C6) and trans at the site of nucleophilic attack (C6-C7) on the three contiguous stereogenic centers in good to excellent yield (up to 94%). The developed strategy was general; the reaction conditions were compatible with hydride, azide, and electron-rich aromatics as nucleophiles. In addition, various methoxylated benzannulated cyclononene acetates could be employed as substrates. Thus, tetrahydro-5 H-benzo[ c]fluorenes could be prepared in four steps from appropriately substituted bromoarenes and benzaldehydes in good yields (up to 56%) with excellent stereo- and regio-control.

The cyclohexene moiety of the tricyclic 6,7-diaryl-tetrahydro-6 H-benzo[ c]chromene core of palodesangrens could be assembled in a biomimetic and step-economical fashion by the Diels-Alder reaction between the electron-rich ( E)-1,3-butadienylarenes as the diene and the electron-deficient chalcones as the dienophile. During the reduction of ketone to the corresponding alcohol by LiAlH 4 , the mixture of endo and exo isomers underwent a novel diastereoconvergent LiAlH 4 -mediated isomerization to install the desired stereochemistry at C10a. Subsequent pyran ring closure under acidic conditions installed the stereochemistry at the remaining C6. Overall, the tricyclic core of palodesangrens could be prepared in three steps and up to 38% yield.

Lamellarin N (Lam N) is a member of an interesting marine natural product class isolated from mollusks and subsequently found in ascidians and sponges. The limited aqueous solubility of Lam N hinders further studies on its cytotoxic activity against cancer cells. In this study, micelles comprising poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) and poly(ethylene glycol)-block-poly(D, L-lactide) (PEG-b-PLA) were developed to circumvent Lam N limited aqueous solubility. The results showed that an increase in the molecular weight of both core materials resulted in higher Lam N loading content, whereas the release of Lam N decreased as a function of molecular weight of PCL and PLA. With less hydrophobic property, PLA micelles provided faster Lam N release. Thus, polymeric micelles could be utilized as controlled-release delivery systems for poorly water soluble Lam N.

Lamellarins, a family of hexacyclic pyrrole alkaloids originally isolated from marine invertebrates, display promising anti-tumor activity. They induce apoptotic cell death through multi-target mechanisms, including inhibition of topoisomerase I, interaction with DNA and direct effects on mitochondria. We here report that lamellarins inhibit several protein kinases relevant to cancer such as cyclin-dependent kinases, dual-specificity tyrosine phosphorylation activated kinase 1A, casein kinase 1, glycogen synthase kinase-3 and PIM-1. A good correlation is observed between the effects of lamellarins on protein kinases and their action on cell death, suggesting that inhibition of specific kinases may contribute to the cytotoxicity of lamellarins. Structure/activity relationship suggests several paths for the optimization of lamellarins as kinase inhibitors.

p-Toluene sulfonic acid (p-TsOH) immobilized either on polystyrene (PS) or silica (Si) was found to be effective in cleaving aromatic ethers containing isopropyl, tert-butyl, allyl, and benzyl groups, as well as mono-, di-, and trimethoxylated benzyl groups, in moderate to excellent yields (54-95%). These protecting groups could be selectively deprotected when they were simultaneously present on the same or different aromatic rings in a substrate.

The syntheses and in vitro antimalarial screening of 50 bridged, bicyclic endoperoxides of types 9-13 are reported. In contrast to antimalarial trioxanes of the artemisinin family, but like yingzhaosu A and arteflene, the peroxide function of compounds 9-13 is contained in a 2,3-dioxabicyclo[3.3.1]nonane system 6. Peroxides 9 and 10 (R(1) = OH) are readily available through a multicomponent, sequential, free-radical reaction involving thiol-monoterpenes co-oxygenation (a TOCO reaction). beta-Sulfenyl peroxides 9 and 10 (R(1) = OH) are converted into beta-sulfinyl and beta-sulfonyl peroxides of types 11-13 by controlled S-oxidation and manipulation of the tert-hydroxyl group through acylation, alkylation, or dehydration followed by selective hydrogenation. Ten enantiopure beta-sulfonyl peroxides of types 12 and 13 exhibit in vitro antimalarial activity comparable to that of artemisinin (IC(50) = 6-24 nM against Plasmodium falciparum NF54). In vivo testing of a few selected peroxides against Plasmodium berghei N indicates that the antimalarial efficacies of beta-sulfonyl peroxides 39a, 46a, 46b, and 50a are comparable to those of some of the best antimalarial drugs and are higher than artemisinin against chloroquine-resistant Plasmodium yoelii ssp. NS. In view of the nontoxicity of beta-sulfonyl peroxides 39a, 46a, and 46b in mice, at high dosing, these compounds are regarded as promising antimalarial drug candidates.