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A novel one-pot synthetic route to the poorly studied 4-heteroaryl-1,2-dihydro-3-benzazepine motif from 3,4-dihydroisoquinolinium compounds is described. The synthetic approach is based on heterocyclic ring expansion of isoquinoline substrates upon reaction with chloromethyl-substituted heterocycles. The scope and limitations of the reaction were investigated to give a series of novel heteroaryl-3-benzazepines. [ABSTRACT FROM AUTHOR]

A new, one-pot approach to 4-acyl-1,2-dihydro-3-benzazepines has been proposed proceeding via a six- to seven-membered heterocyclic ring expansion under the action of α-haloketones. [ABSTRACT FROM AUTHOR]

Abstract: The reactivity of 4-cyano-1,3-dichloro-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine 1 with nucleophiles has been investigated. The different reactivity of the two chlorine atoms in 1 enabled us to obtain, by using different experimental conditions, the mono- and the di-amino-substituted derivatives of 5,6,7,8-tetrahydro-2,7-naphthyridines 2 and 3, respectively. Thus, by carrying out the reaction in a low-boiling solvent and in the presence of a quasi-stoichiometric amount of amine, the mono-substituted derivatives 2 were obtained, which under harsher conditions was transformed into the diamino derivatives 3 when using an excess of amine. During the synthesis of some diamino derivatives 3 a new rearrangement was observed with formation of 1-oxo derivatives of 3,4-dihydro-2,7-naphthyridines 4. The structure of the unexpected compounds 4 was confirmed by X-ray crystallography. A mechanism for the rearrangement is tentatively suggested. [Copyright &y& Elsevier]

Macrophages constitute a major part of tumor microenvironment, and most of existing data demonstrate their ruling role in the development of anti-drug resistance of cancer cell. One of the most powerful protection system is based on heat shock proteins whose synthesis is triggered by activated Heat Shock Factor-1 (HSF1); the inhibition of the HSF1 with CL-43 sensitized A549 lung cancer cells to the anti-cancer effect of etoposide. Notably, analyzing A549 tumor xenografts in mice we observed nest-like pattern of co-localization of A549 cells demonstrating enhanced expression of HSF1 with macrophages, and decided to check whether the above arrangement has a functional value for both cell types. It was found that the incubation of A549 or DLD1 colon cancer cells with either human monocytes or THP1 monocyte-like cells activated HSF1 and increased resistance to etoposide. Importantly, the same effect was shown when primary cultures of colon tumors were incubated with THP1 cells or with human monocytes. To prove that HSF1 is implicated in enhanced resistance caused by monocytic cells, we generated an A549 cell subline devoid of HSF1 which did not respond to incubation with THP1 cells. The pharmacological inhibition of HSF1 with CL-43 also abolished the effect of THP1 cells on primary tumor cells, highlighting a new target of tumor-associated macrophages in a cell proteostasis mechanism. [ABSTRACT FROM AUTHOR]

Treatment of title alkaloid (I) with α-haloketones under conditions A) takes place with a concomitant 1,2-acyl rearrangement to produce ring systems of type (III)/(VI). [ABSTRACT FROM AUTHOR]

A diagram of the chemical structure is presented which shows the synthesis of benzazepines based on the ring expansion.

The different reactivity of the chlorine atoms in title dichloronaphthyridine (I) allows the selective synthesis of mono- and diamino-substituted derivatives (III) as well as (V) and (VI), respectively. [ABSTRACT FROM AUTHOR]

Despite significant progress in the diagnosis and treatment of colorectal cancer, drug resistance continues to be a major limitation of therapy. In this regard, studies aimed at creating combination therapy are gaining popularity. One of the most promising adjuvants are inhibitors of the proteostasis system, chaperone machinery, and autophagy. The main HSP regulator, HSF1, is overactivated in cancer cells and autophagy sustains the survival of malignant cells. In this work, we focused on the selection of combination therapy for the treatment of rectal cancer cells obtained from patients after tumor biopsy without prior treatment. We characterized the migration, proliferation, and chaperone status in the resulting lines and also found them to be resistant to a number of drugs widely used in the clinic. However, these cells were sensitive to the autophagy inhibitor, chloroquine. For combination therapy, we used an HSF1 activity inhibitor discovered earlier in our laboratory, the cardenolide CL-43, which has already been proven as an auxiliary component of combined therapy in established cell lines. CL-43 effectively suppressed HSF1 activity and Hsp70 expression in all investigated cells. We tested the autophagy inhibitor, chloroquine, in combination with CL-43. Our results indicate that the use of an inhibitor of HSF1 activity in combination with an autophagy inhibitor results in effective cancer cell death, therefore, this therapeutic approach may be a promising treatment regimen for certain patients. [ABSTRACT FROM AUTHOR]

Taking into account previously obtained biological results on some polyheterocyclic compounds (containing different heteroatoms) and in particular on several 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4",3":4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidines Ia-v we have carried out the synthesis of twentyone 8-amino-5-isobutyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4",3":4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidines 6. Therefore we have slightly modified the structure of the previously studied I introducing at C-5 an isobutyl group instead of the previously examined isopropyl ones in order to see if this variation (changing a little the lipophilicity) will affect the biological activity. Furthermore thieno[3,2-d]pyrimidine-8-thione 7 and their S-alkylated 8 were synthesized. Finally by alkylation of 5-isobutyl-2,2-dimethyl-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8(9H)-one 3 with alkyl dichlorides (bifunctional reagents) we realized the cyclization of a thiazole or thiazine ring on the [b] side of the pyrimidine ring with formation of the new condensed pentaheterocyclic systems: pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-8-one 11 and pyrano[4''',3''':4'',5'']pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-8-one 12. It was found that some of the synthesized compounds showed interesting antimicrobial activity (by agar diffusion method) against some gram-positive and gram-negative bacilli strains. On the basis of some our previous results we have carried out the synthesis of several new polyheterocyclic compounds with the aim of studying their biological activity. Notwithstanding predictions from in silico tests furnished negative results, we have examined their antimicrobial activity (by agar diffusion methods) observing that several compounds showed very interesting activity. Then we can say that they represent new chemical entities. [ABSTRACT FROM AUTHOR]

The synthesis of some new 'complex' pentaheterocyclic systems, pyrido[3′,2′:4,5]thieno(furo)[2,3‐e][1,2,4]triazolopyrimidines, containing a 1,2,4‐triazolo ring fused at [a] and [b] sides of the pyrimidine ring is described. Interestingly reacting the S,N‐dimethylated compounds 5(c‐h) (containing a furane ring) with hydrazine hydrate, an unusual rearrangement deriving by the breaking of an amide group (HN‐C=O) of the pyrimidine ring has been observed. As a result of the rearrangement 8(9)‐amino‐9(10)‐(methylamino)pyrano[4′′,3′′:4′,5′]pyrido[3′,2′:4,5]furo[3,2‐d]pyrimidin‐7(8)‐ones 9 were obtained: their cyclization led to the formation of new heterocyclic systems, 4(5)‐alkyl‐11(12)‐methylpyrido[3′,2′:4,5]furo[3,2‐d][1,2,4]triazolo[1,5‐a]pyrimidin‐7(8)‐ones 11. The structures of the obtained compounds were confirmed by different physico‐chemical methods. Looking at the syntheses of new 'complex' heterocyclic systems we have prepared some new pentaheterocyclic systems, pyrido[3′,2′:4,5]thieno(furo)[2,3‐e][1,2,4]triazolopyrimidines, containing a 1,2,4‐triazolo ring fused at [a] and [b] sides of the pyrimidine ring. Interestingly in the synthesis of the systems containing the furane ring we have observed an unusual and new rearrangement. The structures of the obtained compounds were confirmed by different physico‐chemical methods. [ABSTRACT FROM AUTHOR]

1-Chloromethyl-3,4-dihydroisoquinolines upon treatment with thioureas under acidic conditions undergo recyclization to afford new β-[ o -(thiazol-4-yl)aryl]ethylamines. [ABSTRACT FROM AUTHOR]

Starting from 7(8)-chlorofuro(thieno)[3,2- d ]pyrimidines 1 , the corresponding 7(8)-hydrazinofuro(thieno)[3,2- d ]pyrimidines 2 were obtained by reaction with hydrazine. By treatment with nitrous acid, compounds 2 gave fused furo- and thieno[2,3- e ]tetrazolo[1,5- c ]pyrimidines 3 T and 4 T in excellent yields, which in solution exist in equilibrium with 7(8)-azidofuro(thieno)[3,2- d ]pyrimidines 3 A and 4 A . Compounds 3 T / 3 A and 4 T / 4 A represent useful substrates for investigating the azide/tetrazole equilibrium: it has been examined as a function of solvent, temperature, and their structure. We have observed that, in solution, in both 3 and 4 the equilibrium was strongly affected by the solvent used. In contrast, X-ray analysis has shown that both thieno[2,3- e ]tetrazolo[1,5- c ]pyrimidines and furo[2,3- e ]tetrazolo[1,5- c ]pyrimidines in solid state exist only in the tetrazole tautomeric form. For this reason the equilibrium constants and the relevant thermodynamic parameters have been calculated in different solvents: finally excellent logarithmic plots of Δ G ° values versus dielectric constants have been observed (slopes 10.00÷10.57; correlation coefficients 0.9962÷0.9999) for a series (seven examples) of furo compounds 3 . [ABSTRACT FROM AUTHOR]

Derivatives of phenanthro[1,2- d ]azepine, a previously unknown heterocyclic system, can be easily obtained from aporphine alkaloids by successive pyridine–pyridine and pyridine–azepine recyclizations. The starting glaucine was used as an illustrative example. [ABSTRACT FROM AUTHOR]

2-Methyl-3,4-dihydro-β-carbolin-2-ium iodide in the reaction with aryl halomethyl ketones is converted into 4- or/and 5-acyl-1,2-dihydroazepino[4,5- b ]indoles depending on the electron donating effect of substituents in the aryl moiety of the halomethyl ketone. [ABSTRACT FROM AUTHOR]

Using glaucine as an example, a convenient access to naphtho[2,1- f ]isoquinoline (litebamine) derivatives is proposed. The synthetic scheme involves a stepwise pyridine–pyridine recyclization of the intermediate N -acylsecoaporphine analogues. [ABSTRACT FROM AUTHOR]

A series of derivatives of a new heterocyclic system, pyrido[3′,2′:4,5]furo[3,2- d ][1,2,4]triazolo[4,3- a ]pyrimidin-7(8)-one 5 , was synthesized starting from the ethyl 1-aminofuro[2,3- b ]pyridine-2-carboxylates 1 . By alkylation with methyl iodide compounds 5 afforded 11(12)-methylpyrido[3′,2′:4,5]furo[3,2- d ][1,2,4]triazolo[4,3- a ]pyrimidin-7(8)-ones 6 . The structure of the obtained compounds besides the spectroscopic methods was confirmed by X-ray analysis. [ABSTRACT FROM AUTHOR]

Hyperglycemia may contribute to the progression of carcinomas by triggering epithelial-to-mesenchymal transition (EMT). Some proteostasis systems are involved in metastasis; in this paper, we sought to explore the mechanism of Hsp70 chaperone in EMT. We showed that knockdown of Hsp70 reduced cell migration capacity concomitantly with levels of mRNA of the Slug, Snail, and Twist markers of EMT, in colon cancer cells incubated in high glucose medium. Conversely, treatment of cells with Hsp70 inducer U-133 were found to elevate cell motility, along with the other EMT markers. To prove that inhibiting Hsp70 may reduce EMT efficiency, we treated cells with a CL-43 inhibitor of the HSF1 transcription factor, which lowered Hsp70 and HSF1 content in the control and induced EMT in carcinoma cells. Importantly, CL-43 reduced migration capacity, EMT-linked transcription factors, and increased content of epithelial marker E-cadherin in colon cancer cells of three lines, including one derived from a clinical sample. To prove that Hsp70 chaperone should be targeted when inhibiting the EMT pathway, we treated cancer cells with 2-phenylethynesulfonamide (PES) and demonstrated that the compound inhibited substrate-binding capacity of Hsp70. Furthermore, PES suppressed EMT features, cell motility, and expression of specific transcription factors. In conclusion, the Hsp70 chaperone machine efficiently protects mechanisms of the EMT, and the safe inhibitors of the chaperone are needed to hamper metastasis at its initial stage. [ABSTRACT FROM AUTHOR]

5,7-Dimethoxy-8-(3,6-diphenylpyridin-2-yl)coumarins were obtained from 5,7-dimethoxycoumarins and 3,6-diphenyl-1,2,4-triazines via the protocol comprising aromatic S N H substitution in the triazine ring followed by the Boger transformation of formed triazine moiety into the pyridine one. The advantages of the suggested method are simple procedures, high yields, and the absence of transition-metal catalysts. [ABSTRACT FROM AUTHOR]