Structure-activity relationships and mechanism of action of antitumor benzo[b]pyrano[3,2-h]acridin-7-one acronycine analogues

The cytotoxic and antitumor activities of cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 3, 6-9 were strongly correlated with their ability to give covalent adducts with purified, as well as genomic, DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical DNA and the leaving ester group at the benzylic position 1 of the drug. A transesterification process of the ester group from position 2 to position 1 in aqueous medium accounted for the intense activity of the cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 10-13. Compounds without acyloxy or hydroxy group at position 1, such as 15, 17, 18, and 22, were inert with respect to DNA and almost devoid of significant cytotoxic activity. Condensation of 5-amino-2,2-dimethyl-2H-chromene (26) with 3-bromo-2-naphthoic acid (27), followed by cyclization, gave access to 6-demethoxy analogues. Diacetate 32 and cyclic carbonate 33, both belonging to the latter series, were less reactive toward DNA and less cytotoxic than their 6-methoxy counterparts 3 and 34. DNA alkylation appears thus to play an important role in the antitumor properties of benzo[b]pyrano[3,2-h]acridin-7-one derivatives.     

Synthesis and cytotoxic and antitumor activity of benzo[b]pyrano[3, 2-h]acridin-7-one analogues of acronycine

Benzo?b?cronycine (6-methoxy-3,3,14-trimethyl-3, 14-dihydro-7H-benzo?bpyrano?3,2-h?cridin-7-one, 4), an acronycine analogue with an additional aromatic ring linearly fused on the natural alkaloid basic skeleton, was synthesized in three steps, starting from 3-amino-2-naphthalenecarboxylic acid (5). Eight 1, 2-dihydroxy-1,2-dihydrobenzo?b?cronycine esters and diesters (17-24) were obtained by catalytic osmic oxidation, followed by acylation. All these compounds were significantly more cytotoxic than acronycine, when tested against L1210 leukemia cells in vitro. The potency of the cyclic carbonate 24 was in the range of the most active drugs currently used in cancer chemotherapy. Two selected diesters (17 and 24) were evaluated in vivo against P388 leukemia and colon 38 adenocarcinoma implanted in mice. Both compounds were markedly active at doses 16-fold lower than the dose of acronycine itself. Against colon 38 adenocarcinoma, compounds 17 and 24 were highly efficient, inhibiting tumor growth by more than 80%. Diacetate 17 was the most active, inhibiting tumor growth by 96% at 6.25 mg/kg, with two of seven mice being tumor-free on day 43.     

Synthesis, cytotoxic activity, and mechanism of action of furo[2,3-c]acridin-6-one and benzo[b]furo[3,2-h]acridin-6-one analogues of psorospermin and acronycine

Compounds possessing the epoxyfuran system present in the natural cytotoxic dihydrofuroxanthone psorospermin (4) fused onto the acridone or benzo[b]acridone chromophores present in the antitumor acronycine (1) and S23906-1 (3) were prepared. The basic furoacridone and benzofuroacridone cores bearing an isopropenyl substituent at a convenient position were synthesized by condensation of 1,3-dihydroxyacridone (7) or 1,3-dihydroxybenz[b]acridin-12(5H)-one (9) with (E)-1,4-dibromo-2-methylbut-2-ene. In both series, the (2R*,1'S*) epoxides, with the same relative configuration as psorospermin, were the most active compounds, exhibiting cytotoxic properties with IC50 values in the 10-100 nM range. As in the acronycine and psorospermin series, the new compounds act through alkylation of the DNA guanine units. However, a strong difference was noted in the DNA alkylation site between the benzopyranoacridone S23906-1, which alkylates DNA guanine units at position N-2 in the minor groove, and the new 13H-benzo[b]furo[3,2-h]acridin-6-one derived epoxide 21, which alkylates DNA guanine units at position N-7 in the major groove.     

Structure activity relationships and mechanism of action of antitumor benzo[b]acronycine antitumor agents

The acridone alkaloid acronycine, isolated from several Sarcomelicope species (Rutaceae) was shown to exhibit a promising activity against a broad spectrum of solid tumors. Nevertheless, subsequent clinical trials only gave poor results, probably due to the moderate potency of this drug. The isolation of the unstable acronycine epoxide from several New-Caledonian Sarcomelicope led to a hypothesis of bioactivation of acronycine by transformation of the 1.2-double bond into the corresponding oxirane in vivo. This hypothesis and the demonstration that acronycine should interact with DNA guided the development of a series of 1.2-dihydroxy-1.2-dihydrobenzo[b]acronycine esters and diesters as novel anticancer drug candidates. In vivo, cis-1.2-diacetoxy-1,2-dihydrobenzo[b]acronycine, selected for further development under the code S 23906-1, demonstated a marked antitumor activity in human orthotopic models of lung, ovarian and colon cancers xenografted in nude mice. The cytotoxic and antitumor activities of these compounds were strongly correlated with their ability to give covalent adducts with purified as well as genomic DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical DNA and the leaving ester group at the benzylic position 1 of the drug.     

噻唑并三嗪类化合物的合成及其基于U2OS-EGFP细胞的抗肿瘤活性

目的探讨7H-噻唑并[3,2-b]-1,2,4-三嗪类化合物的体外肿瘤细胞增殖抑制活性,及初步的构效关系和作用机理。方法以3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮为原料,经环合反应、Williamson反应,合成7H-噻唑并[3,2-b]-1,2,4-三嗪类化合物,考察目标化合物体外肿瘤细胞增殖抑制作用。结果与结论合成了10个7H-噻唑并[3,2-b]-1,2,4-三嗪类化合物,经MS、1H-NMR确证结构。体外抗肿瘤活性研究显示,有4个化合物在50μmol·L~(-1)时对骨肉瘤细胞U2OS-EGFP抑制率高于50%。其中,活性最好的化合物4 d对U2OS-EGFP细胞抑制活性的IC50值为9.824μmol·L~(-1)。分子模拟结果显示,这类化合物作用于ERK1/2,应是一种ERK1/2抑制剂。     

Acronycine revisited: development of benzo[b]acronycine antitumor agents

The acridone alkaloid acronycine, isolated from several Sarcomelicopespecies (Rutaceae) was shown to exhibit a promising activity against a broad spectrum of solid tumors. Nevertheless, subsequent clinical trials gave limited results, probably due to the moderate potency and poor water solubility of this drug. The isolation of the unstable acronycine epoxide from several New-Caledonian Sarcomelicope led to a hypothesis of bioactivation of acronycine by transformation of the 1,2-double bond into the corresponding oxirane in vivo. Consequently, we synthesized a series of cis-1,2-dihydroxy-1,2-dihydroacronycine diesters which exhibited interesting antitumor properties with a broadened spectrum of activity and an increased potency when compared with acronycine. The demonstration that acronycine should interact with DNA prompted us to develop benzo[b]acronycine analogs possessing an additional aromatic ring linearly fused on the natural alkaloid basic skeleton. In vivo, 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine esters and diesters, exemplified by cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine developed under the code S 23906-1, demonstated a marked antitumor activity in human orthotopic models of lung, ovarian and colon cancers xenografted in nude mice. The cytotoxic and antitumor activities of these compounds were strongly correlated with their ability to give covalent adducts with purified as well as genomic DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical DNA and the leaving ester group at the benzylic position 1 of the drug.     

Synthesis and antitumor activity of pyrrolo [3,2-d]pyrimidines

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 25, No. 12, pp. 19–23, December, 1991.     

5H-呋喃并[3,2-g]色烯类化合物的合成及其抗肿瘤活性

目的 设计合成5H-呋喃并[3,2-g]色烯类化合物,并测定其体外抗肿瘤活性。方法 以2’,4’-二羟基苯乙酮为原料,经缩合、催化氢化和 Fries 重排等反应合成目标化合物。采用人骨肉瘤细胞U2OS-EGFP-4A12G对目标化合物的体外抗肿瘤活性进行初步评价。结果与结论 合成了10个未见文献报道的5H-呋喃并[3,2-g]色烯类化合物,其结构经红外光谱、质谱、核磁共振氢谱确证。化合物7a、7e 和 7h 对人骨肉瘤细胞 U2OS-EGFP-4A12G 的抑制活性较强,其IC₅₀值分别为16.53、7.74、13.27 μmol·L^-1。5H-呋喃并[3,2-g]色烯类化合物是一类具有新型骨架结构的抗肿瘤化合物,值得进一步研究。     

Synthesis and antimicrobial activities of novel naphtho[2,1-b]pyran, pyrano[2,3-d]pyrimidine and pyrano[3,2-e][1,2,4]triazolo[2,3-c]-pyrimidine derivatives

The synthesis of new naphtho[1',2':5,6]pyrano[2,3-d]pyrimidines and related heterocycles has been reported. The key intermediate 3-amino-8-bromo-1-(p-methoxyphenyl)-1H-naphtho[2,1-b] pyran-2-carbonitrile (3c) was obtained in one pot synthesis by treating alpha-cyanocinnamonitrile (1c) with 6-bromo-2-naphthol (2). Antimicrobial activity was shown for some of the synthesized compounds.     

Synthesis and antimicrobial evaluation of naphtho[2,1-b]pyrano[2,3-d]pyrimidine and pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives

Several novel naphtho[2,1-b]pyrano[2,3-d]pyrimidines, pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines and their coumarin-3-yl derivatives were synthesized. Some of these derivatives exhibited pronounced antimicrobial activities.     

Synthesis and antitumor activity of certain new thiazolo[2,3-b]quinazoline and thiazolo[3,2-a]pyrimidine analogs

A novel series of thiazolo[2,3-b]quinazoline (16–19, 25–28, and 34–37) and cyclohepta[d]thiazolo[3,2-a]pyrimidine (20–23, 29–32, and 38–41) analogs was designed and synthesized. Structure elucidation of the synthesized compounds was attained by the use of H¹ NMR, C¹³ NMR, and mass spectrometry. The obtained compounds were evaluated for their in vitro antitumor activity using the National Cancer Institute’s 60 cell lines’ panel assay that included nine tumor subpanels, namely, leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancer cells. Most of the investigated compounds showed a remarkable broad-spectrum antitumor activity. Compounds 19, 28, 32, and 34 proved to be 10-, 15-, 2-, and 7-fold more active than 5-FU, with GI₅₀ MG-MID values of 2.4, 1.5, 11.2, and 3.1 μM, respectively.     

Synthesis and antidepressant-like action of 9-alkoxy-7H-furo[3,2-g] chromen-7-ones in mice

The present study describes the chemical synthesis and pharmacological evaluation of a series of 9-alkoxy-7H-furo[3,2-g]-chromen-7-ones. The pharmacological results of these compounds show that nine of them, given orally, reduced the immobility time in the forced swimming test. The results of the open-field test further confirmed that these compounds possessed an antidepressant-like effect. In the 5-hydroxytryptophan induced head-twitch test, 9-(3-chlorobenzyloxy)-7H-furo[3,2-g]chromen-7-one (3 m, 40 mg/kg p. o.) significantly increased the cumulative numberof head twitches. This finding suggested that the antidepressant-like profile seems to involve the serotonergic system as underlying mechanism.     

新型乙酰胆碱酯酶抑制剂7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与生物活性

目的 寻找作为乙酰胆碱酯酶抑制剂的具有新化学结构类型的化合物。方法 采用分子对接的方法寻找新型的乙酰胆碱酯酶抑制剂,设计并合成了10个7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。通过Erlenmeyer-Plöchl反应及缩合反应生成目标化合物6-芳甲基-3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物,其结构采用红外光谱、质谱和核磁共振氢谱确证。采用Ellman方法进行体外抑制乙酰胆碱酯酶活性测试。 结果 合成了10个7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物,体外抑制乙酰胆碱酯酶活性测试结果显示所有目标化合物均具有抑制乙酰胆碱酯酶活性,8个目标化合物在10 μmol.L-1浓度水平抑制活性均超过了50%。结论7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物是潜在的乙酰胆碱酯酶抑制剂,是一类具有新骨架结构的AChE抑制剂。     

Synthesis and antimicrobial activity of new 7 beta-(benzo[a]dihydrocarbazolyloxyacetyl)-substituted cephalosporins

Selected 7beta-(benzo[a]dihydrocarbazolyloxyacetyl)-substituted cephalosporins (1a-e) were synthesised and tested for their antimicrobial activity against Gram-positive and Gram-negative clinical pathogens. All compounds synthesised (1a-e) showed an in vitro antimicrobial activity similar to that of ceftriaxone and cefpirome against the Gram-positive bacteria, and superior to that of penicillin and cefaclor against pen-R Staphylococcus aureus species. Like all beta-lactam agents, compounds 1a-e were in an inactive Minimum Inhibitory Concentration (MIC > 32 microg/ml) against methicillin-resistant S. aureus species. Furthermore, as expected, no cross-resistance was observed against the erythromycin-resistant Staphylococcus pyogenes strain. Finally, it is worth underlining that compounds 1a and 1e showed a similar activity to that of ceftriaxone and superior to cefaclor against penicillin-resistant Streptococcus pneumoniae isolates, a key respiratory tract infection (RTI) causing pathogen difficult to treat with currently marketed antibiotics.     

Synthesis and antitumor activity of pyrano[4′,3′:4,5]pyrido[2,3-b]thieno[3,2-d]-1,2,3-triazine and l,2,3-triazino[4′,5′:4,5¦thieno-[2,3-c]isoquinoline derivatives

Methods for the synthesis of new heterosystems of condensed thieno[3,2-d]-1,2,3-triazines on the basis of pyrido[2,3-b]thiophenes have been developed. The antitumor activity of the synthesized compounds was studied and several compounds possessing low toxicity and moderate antitumor activity were found. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 6, pp. 3–5, June, 2006.     

Synthesis and biological activity of pyrimido[2,1-b][1,3]thiazine, [1,3]thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine derivatives and thiazole analogues.

Some series of thiazolo[3,2-a]pyrimidine, pyrimido[2,1-b] [1,3]thiazine, thiazolo[3,2-a]purine, [1,3]thiazino[3,2-a]purine, thiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine derivatives, variously functionalized, were prepared. The compounds were tested for antimicrobial and antimycotic activity on a number of strains, namely: E. coli, Proteus vulgaris, P. mirabilis, Pseudomonas aeruginosa, Salmonella sp., Staphylococcus aureus, S. faecalis, Bacillus subtilis, Sarcina lutea, Candida albicans, C. tropicalis, Aspergillus sp., and for antiviral activity on Herpes simplex virus Type 1, Vesicular stomatitis virus and Coxsackievirus B5. The compounds proved to be devoid of activity against viruses and gram-negative bacteria, while some of them exhibited modest activity against gram-positive bacterial strains.     

Synthesis and molluscicidal activity of some 1,3,4-triaryl-5-chloropyrazole, pyrano[2,3-c]pyrazole, pyrazolylphthalazine and pyrano[2,3-d]thiazole derivatives

2-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-malononitrile 1a reacts with the arylidenes of malononitrile 2a-d to afford the triaryl-5-chloropyrazoles 3a-d, respectively. 1a reacts with the active methylene pyrazolinones 5a, b and 12a, b to afford different products 8, 9, 10, 11, and 14a, b--depending on the substitution in the pyrazole ring. Compound 1a reacts also with the pyridazinone derivative 15 to afford the phthalazinone 16, and with the thiazolinones 17a-c to afford the pyrano[2,3-d]thiazoles 20a-c, respectively. It reacts also with the malononitrile dimer 21a and with ethyl cyanoacetate dimer 21b to yield the pyrazolyl pyridines 22a, b, respectively. The synthesized compounds showed a moderate molluscicidal activity towards Biomphalaria alexandrina snails.