Abstract:
:Long-term survivors of glioblastoma multiforme (GBM) are at high risk of developing second primary neoplasms, including leukemia. For these patients, the use of classic tyrosine kinase inhibitors (TKIs), such as imatinib mesylate, is strongly discouraged, since this treatment causes a tremendous increase of tumor and stem cell migration and invasion. We aimed to develop agents useful for the treatment of patients with GBM and chronic myeloid leukemia (CML) using an alternative mechanism of action from the TKIs, specifically based on the inhibition of tubulin polymerization. Compounds 7 and 25, as planned, not only inhibited tubulin polymerization, but also inhibited the proliferation of both GMB and CML cells, including those expressing the T315I mutation, at nanomolar concentrations. In in vivo experiments in BALB/cnu/nu mice injected subcutaneously with U87MG cells, in vivo, 7 significantly inhibited GBM cancer cell proliferation, in vivo tumorigenesis, and tumor growth, tumorigenesis and angiogenesis. Compound 7 was found to block human topoisomerase II (hTopoII) selectively and completely, at a concentration of 100 μM.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Puxeddu M,Shen H,Bai R,Coluccia A,Bufano M,Nalli M,Sebastiani J,Brancaccio D,Da Pozzo E,Tremolanti C,Martini C,Orlando V,Biagioni S,Sinicropi MS,Ceramella J,Iacopetta D,Coluccia AML,Hamel E,Liu T,Silvestri R,La Redoi
10.1016/j.ejmech.2021.113532keywords:
["Glioblastoma","Leukemia","Pyrrole","Synthesis","Tubulin"]subject
Has Abstractpub_date
2021-10-05 00:00:00pages
113532eissn
0223-5234issn
1768-3254pii
S0223-5234(21)00381-0journal_volume
221pub_type
杂志文章相关文献
文献大全abstract::In order to study the effect of steric hindrance on competition between two kinds of beta-hydroxylation, a compound bearing on a pyrimidinetrione nucleus both a branched side chain with a tertiary carbon atom in position beta (isobutyl group) and a linear side chain (ethyl group), was selected and administered to rats...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)00110-0
更新日期:2000-01-01 00:00:00
abstract::Pyrrolidinyl- and thiazolidinyl- dipeptide derivatives, featuring either a vinyl sulfone-, a 2-ketobenzothiazole-, a nitrile-, or a benzimidazole group at the C-terminus, were designed and synthesized as potential inhibitors of the prolyl-specific Tc80 proteinase from Trypanosoma cruzi, the agent of Chagas' disease. T...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)00118-5
更新日期:2000-02-01 00:00:00
abstract::Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino or hydroxyl groups with N-tert-butyloxycarbonyl-beta-alanine (Boc-beta-ala; Boc = t-butoxycarbonyl) in the presence of carbodiimide derivatives afforded, after removal of the protecting group, a series of water-soluble compounds (as s...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)00130-6
更新日期:2000-03-01 00:00:00
abstract::To further explore the structure-activity relationships of beta-adrenoceptor (beta-AR) antagonists, a series of 25 para-substituted N-isopropylphenoxy-propanolamines were synthesised, nine of which are new compounds. All have been examined for their ability to antagonise beta(1)-ARs in rat atria and beta(2)-ARs in rat...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(99)00114-2
更新日期:1999-11-01 00:00:00
abstract::Synthesis of palladium(II) complexes of the type [PdLCl(2)] (where L = Schiff bases derived from 2-acetylpyridine and S-methyldithiocarbazate, S-benzyldithiocarbazate or thiosemicarbazide) have been isolated by the reaction of [Pd(DMSO)(2)C1(2)] and respective ligands. The complexes have been characterized by elementa...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)00145-8
更新日期:2000-05-01 00:00:00
abstract::By the hypothesised correlation with the large conductance Ca(++)-activated potassium channel (BK(Ca)) openers NS 004 and NS 1619, bearing a benzimidazolone ring, a series of new 5-(4'-substituted-2'-nitroanilino)-1,2,3-triazoles were synthesised and tested on in vitro isolated vascular preparation. The compounds were...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)00180-x
更新日期:2000-07-01 00:00:00
abstract::Quantum chemical QSAR expressions have been developed for a heterogeneous group of 36 sulfonamides which have been shown to lower intraocular pressure in in vivo tests on animals. It was found, using the ACE statistical technique, that the lowering of intraocular pressure correlated non-linearly with K(I) for carbonic...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)00182-3
更新日期:2000-09-01 00:00:00
abstract::A new family of 1,2,4-thiadiazolidinone derivatives containing the N-benzylpiperidine fragment has been synthesised. The acetylcholinesterase (AChE) inhibitory activity of all compounds was measured using Ellman's method and some of them turned out to be as potent as tacrine. Furthermore, compound 13 was as active as ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)01166-1
更新日期:2000-10-01 00:00:00
abstract::Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the life cycle of the retrovirus, responsible for catalysing the insertion of the viral genome into the host cell chromosome. For this reason it provides an attractive target for antiviral drug design. We synthesized a series of novel...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)01181-8
更新日期:2000-11-01 00:00:00
abstract::A series of 1,2,4-oxadiazolidine-3,5-diones was synthesized and evaluated as oral antihyperglycemic agents in the obese insulin resistant db/db and ob/ob mouse - the two models for Type 2 diabetes mellitus. The majority of the prepared methoxy- and ethoxy-linked oxazole 1,2,4-oxadiazolidine-3,5-diones normalized plasm...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)01191-0
更新日期:2001-01-01 00:00:00
abstract::1,3-Dihydroxy-9,10-anthraquinone (4) was reacted with epichlorohydrin or 1,omega-dibromo-alkane to yield 1-hydroxy-3-(2,3-epoxypropoxy)-9,10-anthraquinone (5) and 1-hydroxy-3-(3-chloro-2-hydroxypropoxy)-9,10-anthraquinone (6) or 1-hydroxy-3-(omega-bromoalkoxy)-9,10-anthraquinone. Ring-opening of the epoxide (5) or 1-h...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)01190-9
更新日期:2000-12-01 00:00:00
abstract::A series of new anti-HIV derivatives containing a novel alpha-thiophenoxyhydroxyethylamide core have been synthesized, using S-phenylbenzenethiosulfonate as the thiosulfenylating reagent. Some of the new synthesized compounds (1a, 1c, 1g, 1i, 1j and 1l) inhibited HIV replication in cell culture assays (syncytia format...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)80031-8
更新日期:1999-07-01 00:00:00
abstract::RO-04-6790 (6a) has been identified in a random screen for 5-HT(6) receptor antagonists. In a medicinal chemistry optimisation program a series of analogs comprising N-heteroaryl- and N-arylbenzenesulfonamides have been synthesised and investigated for their binding affinity. Compounds with a logD profile indicative o...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)01209-5
更新日期:2001-02-01 00:00:00
abstract::A series of 1H-pyrazolo[3,4-d]pyrimidines (3--6) substituted at positions 1 (R(1)=Ph, H, tert-butyl and ribosetribenzoate), 4 (R(2)=chlorine, nitrogen and oxygen nucleophiles), and 6 (dimethylamino) have been synthesized and their effect on the release of histamine from rat peritoneal mast cells measured. After chemic...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(01)01225-9
更新日期:2001-04-01 00:00:00
abstract::A series of O-alkylated tropolones and related alpha-ketohydroxy compounds were evaluated for their biological activities and were shown to present an expected ribonucleotide reductase inhibition and cytotoxicity against some cancer cell lines but no antitubulin activity. Pharmacomodulation studies were realised to un...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(01)01249-1
更新日期:2001-06-01 00:00:00
abstract::The synthesis of some triazolyl-antipyrine derivatives starting from 4-chloroacetamidoantipyrine and 3-(aryloxyalkyl)-4-ethyl/phenyl-5-mercapto-1,2,4-triazoles is described. The chemical structures of the compounds were elucidated by IR, 1H-NMR and mass spectral studies. These compounds were tested for analgesic activ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(01)01252-1
更新日期:2001-07-01 00:00:00
abstract::Some optically active 3-(arylmethylidene)aminoxy- (3a-g, 4a-g) and fluorenylideneaminoxy-2-methylpropionic acids (5, 6), were prepared as analogues of the antiinflammatory arylpropionic acids of type B, in which the aromatic group is substituted by an MAOM moiety. Some of the new compounds, tested in vivo for their an...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(01)01275-2
更新日期:2001-10-01 00:00:00
abstract::A group of 11 derivatives of chelidonine was obtained by acylations and/or alkylations of the secondary hydroxyl group with the aim of testing their biological activity. This paper focuses on the new derivatives influence on CNS in mice. The highest activity was observed for compounds 2c, 3c and 4, which produced anti...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:
更新日期:2001-11-01 00:00:00
abstract::6-(Substituted-phenyl)amino-5,8-quinazolinediones (3) were synthesised by regioselective substitution of 5,8-quinazolinedione (5) with appropriate arylamines in the presence of Ce(III) ions. All synthesised 5,8-quinazolinediones 3 showed a potent and efficacious inhibitory effect on the acetylcholine (ACh)-induced vas...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(01)01290-9
更新日期:2002-01-01 00:00:00
abstract::This paper focuses on the synthesis and the in vitro testing of dual COX-1/COX-2 inhibitors. Starting from structures of non-steroidal anti-inflammatory drugs (NSAIDs) the diaryl methanone element was chosen as a lead. Modifications were carried out on this scaffold to obtain potent inhibitors of the COX enzymes. The ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(01)01330-7
更新日期:2002-02-01 00:00:00
abstract::Ten 6-chlorobenzothiazolyl-2-thiosemicarbazones were synthesised and screened for anticonvulsant and neurotoxic properties. Most of the compounds showed anticonvulsant activity against both maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole screens. Eight compounds have shown good protection in the...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(02)01338-7
更新日期:2002-03-01 00:00:00
abstract::Dual-action agents 5a-f and 12a-f, a beta-lactam antibiotic combined with a cytotoxic agent, mitozolomide (Meto) or temozolomide (Temo), were synthesised. The antibacterial activity (MICs) of the dual-action agents has been determined against a panel of bacteria including several beta-lactamase producing strains. The ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(01)01331-9
更新日期:2002-04-01 00:00:00
abstract::Mannich bases obtained by aminoalkylation of 3H-pyrrolo[3,2-f]quinoline were designed and prepared as potential vasorelaxing agents. Compounds Ia-Va were characterised by IR, 1H-NMR, mass spectral data and elemental analysis; IIb,c-Vb,c were also confirmed by 1H-NMR spectra of reaction mixtures. To estimate their vasc...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(02)01355-7
更新日期:2002-05-01 00:00:00
abstract::The (E)-[2-(4-aminosulfonylphenyl)-1-cyclopentenyl-1-methyliden]-(arylmethyloxy)amines (6a,b), which are the sulfonamidic analogues of the previously described methylsulfonyl derivatives 5a,b, and their corresponding sulfides (7a,b) and sulfoxides (8a,b) were synthesised in order to obtain information about the role p...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(02)01385-5
更新日期:2002-07-01 00:00:00
abstract::A series of nine dimethylamino-chalcone derivatives (1,3-diaryl-propenones) was synthesized and screened as potential inhibitors of NO and PGE(2) production in the RAW 264.7 macrophage cell line. 4-Dimethylamino-2',5'-dimethoxychalcone (6) was found to be the most potent and dual inhibitor (IC(50s) in the submicromola...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(02)01387-9
更新日期:2002-08-01 00:00:00
abstract::A series of bis-phenoxyacetic acids 2 were prepared starting from corresponding unsubstituted/substituted 1,4-quinols 1. The fusion of bis-phenoxyacetic acids 2 with thiocarbohydrazide gave the corresponding bis-[4-amino-5-mercapto-1,2,4-triazol-3-yl-methyleneoxy]phenylenes (3) in a one pot reaction. The reaction of b...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(02)01358-2
更新日期:2002-06-01 00:00:00
abstract::In the present study, a series of 1-substituted-4-hydroxyphthalazines were synthesized and characterized by IR, 1H-NMR and Elemental analysis. The compounds were assayed against seizures induced by maximal electroshock (MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The decr...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(02)01405-8
更新日期:2002-10-01 00:00:00
abstract::The crystal structure of a gp120/CD4/Fab17b complex was analysed leading to the design of several peptide libraries in the hope of obtaining novel gp120/cell membrane receptor interaction inhibitors, especially inhibitors of gp120/CD4 and gp120/chemokine receptor interactions. Syntheses of tri- and tetra- and pentapep...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(02)01412-5
更新日期:2002-11-01 00:00:00
abstract::Several podophyllotoxin derivatives lacking the methylenedioxy group or with different functionalization of the A-ring of the cyclolignan skeleton have been prepared and evaluated for their cytotoxic activities on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28). Most of them maintained their cytotoxicity a...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(02)00007-7
更新日期:2003-01-01 00:00:00
abstract::In the course of a medicinal chemistry program aimed at discovering novel tumour-active rebeccamycin derivatives targeting DNA and/or topoisomerase I, a series of analogues with the sugar residue linked to the two indole nitrogens was recently developed. Two promising drug candidates in this staurosporine-rebeccamycin...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(02)01423-x
更新日期:2002-12-01 00:00:00