Stereoselective Synthesis of Baloxavir Marboxil Using Diastereoselective Cyclization and Photoredox Decarboxylation of l-Serine.

Baloxavir marboxil (1; BXM) is a potent drug used for treating influenza infections. The current synthetic route to BXM (1) is based on optical resolution; however, this method results in the loss of nearly 50% of the material. This study aimed to describe an efficient and simpler method for the synthesis of BXM. We achieved a stereoselective synthesis of BXM (1). The tricyclic triazinanone core possessing a chiral center was prepared via diastereoselective cyclization utilizing the readily available amino acid l-serine. The carboxyl moiety derived from l-serine was removed via photoredox decarboxylation under mild conditions to furnish the chiral tricyclic triazinanone core ((R)-14). The synthetic route demonstrated herein provides an efficient and atomically economical method for preparing this potent anti-influenza agent.

Synthesis of Rupestonic Acid L-Ephedrine Derivatives with Preliminary In vitro Anti-influenza Viral Activity.

BACKGROUND: Influenza virus is a kind of RNA virus. Nowadays, the high incidence of influenza and the morbidity and mortality of epidemic influenza are substantial. It has been reported that one hundred million people in the world are infected with influenza viruses, and two hundred and fifty thousand to five hundred thousand people die from the flu per year. In 2021, the number of infected persons in China was reported to be 654,700, and 0.07% of the infected persons died. The flu has caused a serious threat to human survival. Although several drugs, such as Zanamivir, Oseltamivir, Peramivir, and Laninamivir, have been used in clinics for the treatment of the influenza virus, there are some shortcomings of these drugs. The strain of influenza H5N1 (avian influenza) has been found to resist the effective drug Oseltamivir. Thus, there is an urgent demand to discover new influenza virus inhibitors to overcome the emergence of influenza antigens. AIMS: This study aimed to develop new influenza virus inhibitors based on the rupestonic acid parent core. OBJECTIVE: The rupestonic acid L-ephedrine ester (A) and rupestonic acid L-ephedrine complex (B) were synthesized in this work for the development of influenza virus inhibitors. METHODS: The target compounds were synthesized using rupestonic acid and L-ephedrine as starting materials. Their structures were characterized by 1H NMR and 13C NMR, and the purity was determined by HPLC. Then, their preliminary in vitro influenza activity was evaluated using Oseltamivir as a reference drug. RESULTS: The results showed that the synthesized rupestonic acid L-ephedrine derivatives A and B were more potent influenza virus inhibitors against the strains of A/PR/8/34 (H1N1) and A/FM/1/47 (H1N1) with the IC50 values of 51.0, 51.0 µM and 441.0, 441.0 µM, respectively, than that of rupestonic acid. By comparing the IC50 of compounds A and B, compound A can be regarded as a very promising lead compound for the development of influenza virus inhibitors. CONCLUSION: The rupestonic acid L-ephedrine ester (A) and rupestonic acid L-ephedrine complex (B) were synthesized and characterized using 1H NMR and 13C NMR. Moreover, their purity was determined by HPLC. Both compounds A and B exhibited more potent activities against the strains of A/PR/8/34 (H1N1) and A/FM/1/47 (H1N1) than rupestonic acid. Compound A can be regarded as a very promising lead compound for the development of influenza virus inhibitors. Based on these results, more rupestonic acid derivatives will be designed and synthesized in the future for the development of influenza virus inhibitors.

Synthesis of targeted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines as potential lead molecules with promising anti-breast cancer activity.

A targeted library of substituted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines (prototypes I, II and III), and structurally analogous to tamoxifen have been synthesized as a new class of anti-breast cancer agents. All the prototype molecules exhibited potential antiproliferative activity against ER + ve and ER-ve breast cancer cell lines. Dibenzo[b,f]thiepine prototypes were found to be more active. Of all the compound tested, 14b exhibited potent in-vitro antiproliferative activity at 1.33 µM and 5 µM concentration in MCF-7 and MDA-MB-231 cell lines and was devoid of any cytotoxicity in normal HEK cells even at 50 µM. Cell cycle analysis showed that the compound 14b inhibited cell proliferation due to G0/G1 arrest in MCF-7 cells. Annexin-V FITC and PI staining experiments confirmed that the cell inhibition was primarily due to apoptosis and not by necrosis, which was also supported by LDH release assay experiment. Molecular docking studies showed better binding interaction of the new dibenzo[b,f]thiepine analogue 14b with the estrogen receptor (ER) as compared to 4-hydroxy-tamoxifen and this enhanced binding might be responsible for its estrogen antagonistic activity that induces cell cycle arrest, apoptosis and inhibition of breast cancer cells.

Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy based on Top1 poison-mediated DNA damage. Several novel benzopentathiepines were synthesized and tested as inhibitors of TDP1 using a new oligonucleotide-based fluorescence assay. The benzopentathiepines have IC50 values in the range of 0.2-6.0 µM. According to the molecular modeling, the conformational flexibility of the dibutylamine group of the most effective inhibitor (3d) allows it to occupy an advantageous position for effective binding compared to its cyclic counterparts. The study of cytotoxicity of these compounds revealed that all compounds cause an apoptotic cell death in MCF-7 and Hep G2 cells. Therefore the new class of very effective inhibitors of TDP1 was elaborated.

Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for α(1)-adrenoceptors.

A series of 1-(10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine analogues substituted in the 8-position of the 10,11-dihydrodibenzo[b,f]thiepine scaffold with aryl, heteroaryl, amine, and amide substituents are described. The compounds were designed using the previously reported Liljefors-Bøgesø pharmacophore model for dopamine D(2) and α(1)-adrenoceptor antagonists, with the aim of obtaining selective α(1)-adrenoceptor antagonists suitable for development as radioligands for imaging of central α(1)-adrenoceptors by positron emission tomography. Sixteen aryl and heteroaryl substituted octoclothepin analogues were prepared by a convergent synthesis via coupling of 1-methyl-4-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10,11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine with aryl and heteroaryl halides under palladium catalysis. The most selective compound obtained, (S)-N-((11-(4-methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thiepin-2-yl)methyl)isobutyramide (S)-35, showed a similar subnanomolar affinity compared to α(1a), α(1b), and α(1d)-adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D(2), 5-HT(2C), and H(1) receptors, respectively.

A new concise strategy for synthesis of dibenzo[b,f]thiepins and related fused symmetrical thiepin derivatives.

A new strategy for preparation of dibenzo[b,f]thiepins and related fused systems in good overall yields is described, featuring ortho-metalation of aromatic or heterocyclic aldehyde acetals followed by treatment with bis(phenylsulfonyl) sulfide for construction of the required bis(aryl)- or bis(heteroaryl) sulfide precursors, which were thereafter subjected to deacetalization, and finally McMurry coupling as the ring-forming step.

Synthesis and chemistry of enantiomerically pure 10,11-dihydrodibenzo[b,f]thiepines.

Several chiral thiepines were efficiently constructed using sulfur diimidazole in combination with a variety of bislithiated carbon fragments. The sulfur atom in these thiepines is found to be unusually unreactive compared to diphenylsulfide.

Two routes to (11,12)-dihydrodibenzo[c,g][1,2]dithiocine.

The title compound is made by two routes. One route features the separate introduction of two sulfur atoms and a double Pummerer reaction while the other route contains a direct introduction of both sulfur atoms using disulfur diimidazole.

A new class of calcium antagonists. 2. Synthesis and biological activity of 11-[[4-[4-(4-fluorophenyl)-1-piperazinyl]butyryl]amino]-6,11- dihydrodibenzo[b,e]-thiepin maleate and related compounds.

A series of [(epsilon-aminoalkanoyl)amino]-6,11- dihydrodibenzo[b,e]thiepins and -5H-dibenzo[a,d]cycloheptenes and related compounds were synthesized and evaluated for calcium antagonistic activity by calcium-induced constriction of potassium-depolarized rat aorta. Semiempirical molecular orbital calculations of the dibenzotricyclic systems indicated that calcium antagonistic activity increased with a decrease of the angle between the planes of the two phenyl rings. AM1 net charge calculations showed that a neutral or positive charge distribution in the bridge portion was necessary for activity. 11-[[4-[4-(4-Fluorophenyl)-1- piperazinyl]butyryl]amino]-6,11-dihydrodibenzo[b,e]thiepin maleate (16, AJ-2615) showed a more gradual and longer lasting antihypertensive effect than diltiazem and nifedipine in spontaneously hypertensive rats (SHR) administered orally. Compound 16 also possessed antianginal effects in methacholine-induced ST elevation and vasopressin-induced ST depression tests in rats. The alteration of the dibenzotricyclic system of 16 to 5H-dibenzo[a,d]cycloheptene (19, 5-[[4-[4-(4-fluorophenyl)-1-piperazinyl]-butyryl]amino]-5H- dibenzo[a,d]cycloheptene) resulted in selectivity for cardiac tissue over vascular tissue, thereby conferring antianginal activity without an effect on blood pressure. Antianginal potencies of 16 and 19 were equal to or somewhat more potent than those of diltiazem.

A new class of calcium antagonists. Synthesis and biological activity of 11-[(omega-aminoalkanoyl)amino]-6,6a,7,8,9,10,10a,11-octahydrodibenzo [b,e]thiepin derivatives.

A series of 11-[(omega-aminoalkanoyl)amino]-6,6a,7,8,9,10,10a,11- octahydrodibenzo[b,e]thiepin derivatives were prepared and found to be a structurally new class of calcium antagonists. The structure-activity relationship studies indicated that the optimum was (6aR*,10aR*,11R*)-11-[[4-[4-(4-fluorophenyl)-1- piperazinyl]butyryl] amino]-6,6a,7,8,9,10,10a,11-octahydrodibenzo[b,e]thiepin (31,pA2 8.16), which was superior to diltiazem (pA2 7.42) in calcium antagonistic activity. Compound 31 showed antihypertensive activity in anesthetized rats, without a significant effect on the heart rate. It had also antianginal effects in vasopressin-induced ST-depression and methacholine-induced ST-elevation testings in rats. These potencies of 31 were essentially equal to those of diltiazem.

Tricyclic triarylethylene antiestrogens: dibenz[b,f]oxepins, dibenzo[b,f]thiepins, dibenzo[a,e]cyclooctenes, and dibenzo[b,f]thiocins.

The bridging groups O, S, CH2CH2, and SCH2 were used to produce a series of 26 tricyclic triarylethylenes. Their in vitro binding to rat uterine estrogen receptor was measured in a competitive binding assay. Antifertility and uterotrophic tests in rats showed that antiestrogenic activity was present. The most interesting series had a basic side chain, and the most potent compounds were 3-[2-(dimethylamino)ethoxy] -10-ethyl-11-(4-hydroxyphenyl)dibenzo[b,f]thiepin (7b) and 3-[2-(dimethylamino)ethoxy]-11-ethyl-12-(4-hydroxyphenyl)-5,6-dihydrodibenzo[a,e]-cyclooctene (7c), which had good binding (approximately 50% relative to estradiol) and good antiestrogenic activity (ca. one-half of the potency of tamoxifen, III). In this series, the O-bridged compound was the least active, and this is interpreted in terms of the flatness of the dibenzoxepin ring system. Sedative activity was found in some of the compounds.

Tricyclics with analgesic and antidepressant activity. 2. [[(Alkylamino)ethyl]thio]dibenzo[b,f]thiepins and 10,11-dihydro derivatives.

A series of [[(alkylamino)ethyl]thio]dibenz[b,f]thiepins (III) and their 10,11-dihydro derivatives (IV) was synthesized and subjected to broad analgesic/CNS screening. Preliminary results indicated a combination of analgesic/antidepressant profiles, similar to that observed for the [[(alkylamino)ethyl]thio]dibenz[b,f]oxepins (I) and their corresponding dihydro derivatives (II). The most active congener from the present series, 10b, shows an antinociceptive potency in the pentazocine range as assessed by phenyl-p-quinone-induced writhing (PQW) and tail flick in mice. It is also more than twice as active as imipramine in preventing tetrabenazine-induced ptosis (TBZ), a test widely recognized to be of predictive value for clinically efficacious antidepressants.

Synthesis and antiinflammatory activity of 6,11-dihydro-11-oxodibenzo[b,e]thiepinalkanoic acids and related compounds.

Acetic acid derivatives of tricyclic systems, such as 6,11-dihydro-11-oxodibenzo[b,e]thiepin, 4,10-dihydro-4-oxo-thieno[2,3-c][1]benzothiepin, dibenzo[b,f]thiepin, dibenz[b,f]oxepin, etc., were synthesized and assayed for antiinflammatory activity. One of the compounds, 6,11-dihydro-11-oxodibenzo[b,e]thiepin-3-acetic acid (52), was chosen for evaluation in man on the basis of high antiinflammatory activity in both short- and long-term animal assays and a low gastric irritation liability in rats and dogs.

8-chloro-(S)- and -(R)-10-((S)-and -(R)-3'-methylethylaminopyrrolidino)- 10,11-dihydrodibenzo(b,f)thiepins. Synthesis and pharmacological studies.

The synthesis for 8-chloro-(S)- and -(R)-10-[(S)- and -(R)-3'-methylethylaminopyrrolidino]-10,11-dihydrodibenzo[b,f]thiepins is presented. The absolute configuration at position 3' of the aminopyrrolidino side chain is known from synthesis and corresponds to the asymmetric carbon atom in (S)- or (R)-aspartic acid. The absolute configuration at C-10 of the dihydrodibenzo[b,f]thiepin ring system was deduced from ORD-CD analysis coupled with degradation of partially resolved (+)-8-chloro-10-amino-10,11-dihydrodibenzo[b,f]thiepin to (+)-(S)-1,2-diphenylethylamine. The four isomers were studied in mice for their ability to block conditioned avoidance responding, antagonize oxotremorine, and act as analgetics and anticonvulsants. These compounds were found to be nonselective antagonists of histamine, acetylcholine, and BaCl2 in vitro. The compounds exerted effects similar to those of chlorpromazine. Stereoselective differences in activity between diastereoisomers, rather than between enantiomorphs, were generally observed.