Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design,Synthesis, In Vitro,and In Silico Study

Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC₅₀ of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC₅₀ = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC₅₀ = 0.093 µM) compared to Sorafenib (IC₅₀ = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds.     

Synthesis,antiproliferative activity, 3D-QSAR,and molecular docking studies of novel L-carvone-derived pyrimidine-urea compounds

To explore novel natural product-based nitrogen-containing heterocyclic compounds with antiproliferative activity, 20 L-carvone-derived pyrimidine-urea compounds 4a–4t were synthesized through the multi-step reaction of L-carvone, and structurally characterized by Fourier transform infrared (FT-IR), hydrogen-1 nuclear magnetic resonance (¹H-NMR), Carbon-13 nuclear magnetic resonance (¹³C-NMR), and High-resolution mass spectrometry (HRMS). Besides, the in vitro antiproliferative activity of the target compounds against HepG2, Hela, and MCF-7 cells was evaluated by methyl thiazolyl tetrazolium (MTT) assay. According to the results, the target compounds showed certain inhibitory activities against the tested cancer cell lines, and five compounds ( 4b , 4h , 4k , 4l , and 4t ) exhibited better inhibition activities against Hela cells than the positive control ( 5-FU ). Among them, compound 4b held significant antiproliferative activities against Hela and HepG2 cells, and thus deserved further study as a leading compound of new anticancer drugs. In addition, an effective and reasonable three-dimensional quantitative structure-activity relationships (3D-QSAR) model was built by the Comparative molecular field analysis (CoMFA) method to analyze the relationship between the structures of the target compounds and their antiproliferative activities (expressed as pIC₅₀) against Hela cells, and proven to have good predictive ability. Molecular docking was carried out to study the possible binding modes of compound 4b and Survivin, and it was found that compound 4b could be well embedded into the active site, along with the formation of several hydrogen bonds and hydrophobic interactions.     

Synthesis and antiproliferative evaluation of glucosylated pyrazole analogs of K252c

Pyrazole analogs of the staurosporine aglycon K252c were recently described as potent inhibitors of the three Pim protein kinase isoforms. To evaluate the impact of the introduction of a sugar moiety on the biological activities of this heterocyclic scaffold, four new glucosylated pyrazole analogs of K252c were synthesized. Their biological evaluation demonstrated that most active compounds 11 and 19 substituted by a β-d-glucosyl moiety at N12 or N13 positions exhibited antiproliferative activities toward HCT116 cells.     

Synthesis and antiproliferative activities of thioxoflavonoids on three human cancer cells

Two series of fifteen novel thioxoflavonoids 2a-2h and 4a-4g were synthesized from corresponding flavonoids 1a-1h and 3a-3g by reacting with Lawesson’s reagent, respectively. Their in vitro antiproliferative activities were evaluated on a panel of three human cancer cell lines (Hela, HCC1954 and SK-OV-3) using cell counting kit-8 (CCK-8) assay. The results showed that most of the target compounds exhibited moderate to good antiproliferative activities against the three human cancer cell lines. In particular, thioxoflavonoids 2f and 2g showed the strongest antiproliferative activity on all three human cancer cell lines with IC₅₀ values ranging from 3.34 to 4.67 μM, 4f showed the best antiproliferative activity on Hela cells (IC₅₀ 2.30 μM), 2e showed the best antiproliferative activity on HCC1954 cells (IC₅₀ 2.13 μM) and SK-OV-3 cells (IC₅₀ 2.33 μM). The antiproliferative activities may be involved in their antioxidant activity, which can be speculated by their ability to scavenge free radicals and by their capacity of affecting key redox enzymes.     

Palladium complexes of bidentate pyridine N‐heterocyclic carbenes: Optical resolution,antimicrobial and cytotoxicity studies

A series of bidentate pyridine‐functionalized palladium N‐heterocyclic carbene (Pd NHC) complexes with various wingtip substituents (R = methyl, phenyl and tert‐butyl) have been synthesized and evaluated for their potential biomedical applications as antimicrobials and antiproliferative drug candidates. The obtained Pd NHC complexes were applied in a standard broth microdilution assay for determination of their antimicrobial activities against thirteen strains of pathogenic microorganisms. In addition to that, cytotoxic activities of the Pd NHC complexes were also evaluated against three human cancer cell lines, namely breast (MCF‐7), colon (HCT116) and oral (H103) cancer cells, using a standard MTT assay. Upon coordination to palladium, the Pd NHC complexes show significant antimicrobial activities with minimum inhibitory concentrations in the micromolar range, and they are cytotoxic to the tested carcinomas with IC₅₀ ranging from 13 to 38 μM. Evidences for influence of both wingtip substituents and optical isomerism on the biological activities of the complexes have been found.     

Carotenohematoporphyrins as Tumor-Imaging Dyes. Synthesis and In Vitro Photophysical Characterization*

Multichromophoric dyes for use in tumor imaging have been synthesized and photophysically characterized. Structurally, these dyes are dyads and triads that consist of one or two carotenoid polyenes covalently attached to hematoporphyrin (HP) or hematoporphyrin dimethyl ester (HPDME) moieties via ester linkages. The ground-state absorption of each compound shows that the electronic interaction between the chromophores is small. The fluorescence quantum yield for the dyad monocar-oteno- HPDME is 0.033 and the dicaroteno-HPDME triads have yields between 0.016 and 0.007, all of which are reduced with respect to the parent compound HPDME (0.09). Global analysis of the transient fluorescence decays of the dyads and triads requires two exponential components (?5–6ns and ?1–2ns) to fit the data, while a single exponential component with a lifetime of 9.3 ns describes the decay data of the parent HPDME. Possible mechanisms for the observed porphyrin fluorescence quenching by the nearby carotenoid are discussed. Nanosecond transient absorption reveals a carotene triplet with maximum absorption at 560 nm and a 5.0 μs lifetime. No transient was detected at 450 nm, indicating rapid (10 ns) triplet energy transfer from the hematoporphyrin to the carotenoid moieties in fluid as well as in rigid media. The yield of triplet energy transfer from the porphyrin to the carotenoid moiety is unity. Singlet oxygen, O₂(¹δ_g), studies support the transient absorption data, as none of these compounds is capable of sensitizing O₂(¹δ_g). Liposome vesicles were used to study the photophysical characteristics of the dyes in phospholipid membranes. Singlet oxygen was not sensitized by the dyads and triads in liposomes. Transient absorption measurements suggest that the triads are substantially aggregated within the phospholipid bilayer, whereas aggregation in the dyads is less severe.     

Supramolecular triads bearing porphyrin and fullerene via ‘two-point’ binding involving coordination and hydrogen bonding

Supramolecular triads composed of fullerene (C₆₀) as primary electron acceptor, zinc porphyrin (ZnP) as primary electron donor, and either a ferrocene (Fc), or N,N-dimethylaminophenyl (DMA), or N,N-diphenylaminophenyl (DPA) entity as a second electron donor were constructed via a ‘two-point’ binding motif involving axial coordination and hydrogen bonding. The B3LYP/3-21G(*) optimized structures revealed disposition of the three entities of the triads in a triangular fashion. The redox behavior of the different components was studied using cyclic voltammetry in o-dichlorobenzene containing 0.1 M (n-C₄H₉)₄NClO₄. The oxidation potentials of the second electron donor followed the trend: Fc<DMA<DPA, and the free-energy calculations suggested the possibility of the occurrence of sequential hole transfer in these triads. Efficient electron transfer from the excited singlet state of zinc porphyrin to the fullerene entity was observed in all of the studied triads in o-dichlorobenzene. Longer charge-separated states were observed for zinc porphyrin with a carboxylic acid compared with that having an amide group. The ratios of the experimentally determined forward to reverse electron transfer rates, k_CS/k_CR were evaluated to be 10³ for triads formed by zinc porphyrin with a carboxylic acid, suggesting charge stabilization in these triads.     

Synthesis, structure, and in vitro antiproliferative activity of cyclic hypervalent organobismuth(III) chlorides and their triphenylgermylpropionate derivatives

Six compounds of cyclic hypervalent organobismuth(III) chlorides and triphenylgermylpropionates bearing a nitrogen or sulfur atom as intramolecular coordination atom have been synthesized and characterized. The results of single-crystal X-ray analysis reveal that the eight-membered tetrahydroazabismocine rings are highly flexible. The Bi-S or Bi-N bond lengths in the thiabismocine or azabismocine derivatives are dependent on how the substituted groups are acting on the Bi, S or N atom. The replacement of the chlorine atom in azabismocine and thiabismocine with the triphenylgermylpropionic group (Ph₃GeCH₂CH₂COO) leads to the lengthening of Bi-N and Bi-S bond. The substituents connected with the nitrogen atom also have an effect on the Bi-N bond length of azabismocine. For example, a cyclohexyl group has electron-donating ability higher than a phenyl group; the replacement of the former by the latter would lead to the decline of Bi-N bond length and increase of C_Ar-Bi-C_Ar angle in the eight-membered ring. The in vitro antiproliferative activities of the fabricated materials were compared on gastric carcinoma cells by means of the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) method. It was found that the compounds show antiproliferative activity on gastric carcinoma cells (MGC-803) much higher than that of cisplatin. Moreover, there is enhancement of antiproliferative activity when the chlorine atom of the bismocine compounds is replaced by the triphenylgermylpropionic group, giving a low IC₅₀ value of 0.7 μM for thiabismocine triphenylgermylpropionate.     

Silver(I) complexes based on novel tripodal thioglycosides: synthesis, structure and antimicrobial activity

The reaction of tris(2-bromoethyl)amine hydrobromide with sugar thiols or thioacetates leads to the formation of novel carbohydrate substituted tripodal NS₃ ligands. Complexation with silver(I) ions gives stable complexes. NMR, X-ray, MS and EXAFS studies indicate their mononuclear C₃-symmetric structure. The highly water soluble complexes formed from the unprotected ligands show a wide spectrum of effective antimicrobial activities and their use lowers the cytotoxic and antiproliferative activities compared to the free silver salts.     

Synthesis of 4-aryl-6-indolylpyridine-3-carbonitriles and evaluation of their antiproliferative activity

A novel class of 6-indolypyridine-3-carbonitrile derivatives were synthesized and evaluated for antiproliferative activities to establish structure–activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, ethyl cyanoacetate, and ammonium acetate in the presence of piperidine as a catalyst, using a microwave irradiation method or a traditional thermal method. This was followed by chlorination for compounds 13a–e and subsequent nucleophilic substitution of the chlorine group by ethylenediamine at C₂ position of the pyridine ring. The antiproliferative activity of these new nicotinonitriles was evaluated against human ovarian adenocarcinoma (SK-OV-3), breast adenocarcinoma (MCF-7), and cervix adenocarcinoma (HeLa) cells. Among all compounds, 2-((2-aminoethyl)amino)-4-aryl-6-indolylnicotinonitriles series (15a, 15b, 15d, and 15e) exhibited higher antiproliferative activity on the three cancer cell lines with IC₅₀ values of 4.1–13.4 μM.     

Energy‐Funneling‐Based Broadband Visible‐Light‐Absorbing Bodipy–C60 Triads and Tetrads as Dual Functional Heavy‐Atom‐Free Organic Triplet Photosensitizers for Photocatalytic Organic Reactions

C₆₀–bodipy triads and tetrads based on the energy‐funneling effect that show broadband absorption in the visible region have been prepared as novel triplet photosensitizers. The new photosensitizers contain two or three different light‐harvesting antennae associated with different absorption wavelengths, resulting in a broad absorption band (450–650 nm). The panchromatic excitation energy harvested by the bodipy moieties is funneled into a spin converter (C₆₀), thus ensuring intersystem crossing and population of the triplet state. Nanosecond time‐resolved transient absorption and spin density analysis indicated that the T₁ state is localized on either C₆₀ or the antennae, depending on the T₁ energy levels of the two entities. The antenna‐localized T₁ state shows a longer lifetime (τ_T=132.9 μs) than the C₆₀‐localized T₁ state (ca. 27.4 μs). We found that the C₆₀ triads and tetrads can be used as dual functional photocatalysts, that is, singlet oxygen (¹O₂) and superoxide radical anion (O₂ ^{. ?}) photosensitizers. In the photooxidation of naphthol to juglone, the ¹O₂ photosensitizing ability of the C₆₀ triad is a factor of 8.9 greater than the conventional triplet photosensitizers tetraphenylporphyrin and methylene blue. The C₆₀ dyads and triads were also used as photocatalysts for O₂ ^{. ?}‐mediated aerobic oxidation of aromatic boronic acids to produce phenols. The reaction times were greatly reduced compared with when [Ru(bpy)₃Cl₂] was used as photocatalyst. Our study of triplet photosensitizers has shown that broadband absorption in the visible spectral region and long‐lived triplet excited states can be useful for the design of new heavy‐atom‐free organic triplet photosensitizers and for the application of these triplet photosensitizers in photo‐organocatalysis.     

Heterocyclic o-Chloroaldehydes as Synthons in Organic and Inorganic Sulfur Chemistry

Abstract

Many heterocyclic o-chloroaldehydes are easy to prepare, for example via the Vilsmeier chloroformylation reaction. Due to the electron withdrawing effect of the formyl group, the halogen atom is normally a nucleofuge. This can be used to prepare a range of o-substituted heterocyclic aldehydes showing interesting rearrangement reactions. Such types of compounds are also useful as starting materials for the preparation of annelated heterocyclic systems.

We have demonstrated that heterocyclic mercapto groups can be protected as t-butylthioethers. Furthermore, we have found that thiolation of heterocyclic systems containing reactive halogen substituents can conveniently be carried out via the easily prepared t-butylsulfides.

This method has been used in the preparation of a number of N₂S₂-ligands. The resulting transition metal N₂S₂-complexes have been used in the study of model systems for one of the active sites in cytochrome c oxidase. The method also gives access to polymeric heterocyclic multisulfur transition metal complexes with high electrical conductivity.     

Molybdenum pentachloride (MoCl5) or molybdenum dichloride dioxide (MoO2Cl2): advanced catalysts for thioacetalization of heterocyclic, aromatic and aliphatic compounds

A new, convenient and mild method for thioacetalization of heterocyclic, aromatic and aliphatic compounds catalyzed by MoCl₅ or MoO₂Cl₂ is described. This novel method is important for the synthesis of the difficult to prepare heterocyclic thioacetals such as the pterin thioacetals and it offers significant advantages such as high conversion, short reaction times and simplicity in operation.     

Cooperativity between the Halogen Bond and the Hydrogen Bond in H3N⋅⋅⋅XY⋅⋅⋅HF Complexes (X,Y=F,Cl, Br)

Ab initio calculations are used to provide information on H₃N???XY???HF triads (X, Y=F, Cl, Br) each having a halogen bond and a hydrogen bond. The investigated triads include H₃N???Br₂‐HF, H₃N???Cl₂???HF, H₃N???BrCI???HF, H₃N???BrF???HF, and H₃N???ClF???HF. To understand the properties of the systems better, the corresponding dyads are also investigated. Molecular geometries, binding energies, and infrared spectra of monomers, dyads, and triads are studied at the MP2 level of theory with the 6‐311++G(d,p) basis set. Because the primary aim of this study is to examine cooperative effects, particular attention is given to parameters such as cooperative energies, many‐body interaction energies, and cooperativity factors. The cooperative energy ranges from ?1.45 to ?4.64 kcal mol^?1, the three‐body interaction energy from ?2.17 to ?6.71 kcal mol^?1, and the cooperativity factor from 1.27 to 4.35. These results indicate significant cooperativity between the halogen and hydrogen bonds in these complexes. This cooperativity is much greater than that between hydrogen bonds. The effect of a halogen bond on a hydrogen bond is more pronounced than that of a hydrogen bond on a halogen bond.     

Design,synthesis and antiproliferative activity against human cancer cell lines of novel benzo-, benzofuro-, azolo- and thieno-1,3-thiazinone resorcinol hybrids

In this paper we report the design and synthesis of novel derivatives of the 4H-3,1-benzothiazinone type and heterocyclic analogues, i.e. benzofuro-, azolo- and thieno-1,3-thiazin-4-ones possessing 2,4-dihydroxyphenyl substituent. The compounds were obtained by the one-step reaction of aminobenzamides or heterocyclic aminocarboxamides with aryl-modified sulfinylbis[(2,4-dihydroxyphenyl)methanethione]. Evaluation of their antiproliferative potency against human cancer cell lines showed that the activity of some analogues was similar to that of cisplatin. The highest activity and low toxicity were found for 6-tert-butyl-2-(5-chloro-2,4-dihydroxyphenyl)-4H-thieno[3,2-d][1,3]thiazin-4-one. The structure–activity elucidation reveals that the most active compounds are those with a thienothiazin-4-one and benzofuro[3,2-d][1,3]thiazin-4-one skeleton and the presence of the hydrophobic substituent (Et, Cl) in the benzenediol moiety increases their antiproliferative potency. The ADMET properties of selected compounds including metabolic stability and toxicity profile were estimated in silico.     

One‐pot carboxylative cyclization of propargylic alcohols and CO2 catalysed by N‐heterocyclic carbene/Ag systems

A series of N ‐heterocyclic carbene (NHC)/Ag systems were developed for the carboxylative assembly of propargylic alcohols and carbon dioxide (CO₂). With the catalysis of these catalytic systems, a variety of target α‐alkylidene cyclic carbonates could be obtained smoothly under atmospheric CO₂ pressure in straightforward one‐pot processes. Particularly, these reactions could be performed without any stoichiometric addition of bases or additives. Further mechanistic investigation reveals that the excellent activities are attributed to the effective activations of CO₂ accomplished by the NHCs via the formation of the NHC‐CO₂ adducts.     

New 5-(2-ethenylsubstituted)-3(2H)-furanones with in vitro antiproliferative activity

A convenient route to new 3(2H)-furanones is described through hydrogenolysis and subsequent acidic hydrolysis of isoxazoles. The antiproliferative activity of title compounds were evaluated against leukemia-, carcinoma-, neuroblastoma-, and sarcoma-derived human cell lines in comparison to the natural compound geiparvarin. The structure activity relationship indicated that the maximum in vitro antiproliferative activity correlates with the presence of a heterocyclic ring on the ethenyl moiety.     

Synthesis and antiproliferative activities of aminoalkylated polymethoxyflavonoid derivatives

A series of novel aminoalkylated polymethoxyflavonoid derivatives 3–11 was synthesised from 5-hydroxy-3,7,3′,4′-tetramethoxyflavonoid (1) through extending alkoxy chain at the 5-position, and introducing amine hydrogen bond receptor at the end of the side chain. Their antiproliferative activities were evaluated in vitro on a panel of three human cancer cell lines (Hela, HCC1954 and SK-OV-3). The results showed that all the target compounds exhibited antiproliferative activities against investigated cancer cells with IC₅₀ values of 9.51–53.33 μM. Compounds 5, 7, 8, 11 on Hela cells and compounds 4–9, 11 on HCC1954 exhibited more potency as compared to positive control cis-Platin.     

Synthesis and antitumor evaluation of some new derivatives and fused heterocyclic compounds derived from thieno[2,3‐b]pyridine

On the basis of the proven activity of thieno[2,3‐b]pyridines as anticancer, we have designed to synthesize a novel several heterocyclic compounds utilizing thieno[2,3‐b]pyridine as a skeleton through various chemical reactions. The synthesized compounds bear rings that are either directly attached to the thieno[2,3‐b]pyridine as in compounds 4 to 6 and 9 or connected through an amide bridge as compounds 2 , 3a ‐ b , 7 , and 8 . As well as, compounds 10 , 12 to 28 , 30 , 31 , and 33 to 36 bear fused rings to the thieno[2,3‐b]pyridine backbone. The newly synthesized compounds were screened for their antiproliferative activity in vitro against hepatocellular carcinoma (HepG‐2) and breast cancer (MCF‐7) compared with the standard drug (doxorubicin). Compounds 3b , 4 , 6 , 22 , and 28 exhibited promising growth inhibitory effect toward both HepG‐2 and MCF‐7 cell lines with IC₅₀ values ranging from 5.88 to 11.70 μg/mL and 9.64 to 15.10 μg/mL, respectively.     

Syntheses of Acyclic and Macrocyclic Compounds Derived from 9,9-Diethylfluorene (Part I)

A series of new 9,9-diethylfluorenes consisting of three side-arms each bearing a heterocyclic, bis(carboxymethyl)amino, bis(carbamoylmethyl)amino, bis(ethoxycarbonylmethyl)amino or an amino group were prepared on the basis of 2,4,7-tris(bromomethyl)-9,9-diethylfluorene. Imidazolyl, benzimidazolyl, pyrazolyl, pyrrolyl, 1,3-dioxoisoindolyl and pyridinium groups were taken into account as heterocyclic units, attached to the aromatic skeleton via −CH₂−, −CH₂NHCH₂− or −CH₂N=CH− linkers. In addition to the seventeen 2,4,7-trisubstituted 9,9-diethylfluorenes, two macrocyclic compounds were prepared on the basis of 2,7-bis(aminomethyl)-9,9-diethylfluorene. The excellent yield of the macrocyclization reaction is worth a special mention. Both the acyclic and the macrocyclic fluorene-based compounds have, among other things, the potential to act as artificial receptors for different substrates in analogy to the known receptors consisting of a benzene or biphenyl core.