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1.
J Nat Prod ; 83(4): 937-954, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32196334

RESUMO

The natural products combretastatin A-1 (CA1) and combretastatin A-4 (CA4) function as potent inhibitors of tubulin polymerization and as selective vascular disrupting agents (VDAs) in tumors. Bioreductively activatable prodrug conjugates (BAPCs) can enhance selectivity by serving as substrates for reductase enzymes specifically in hypoxic regions of tumors. A series of CA1-BAPCs incorporating nor-methyl, mono-methyl, and gem-dimethyl nitrothiophene triggers were synthesized together with corresponding CA4-BAPCs, previously reported by Davis (Mol. Cancer Ther. 2006, 5 (11), 2886), for comparison. The CA4-gem-dimethylnitrothiophene BAPC 45 proved exemplary in comparison to its nor-methyl 43 and mono-methyl 44 congeners. It was stable in phosphate buffer (pH 7.4, 24 h), was cleaved (25%, 90 min) by NADPH-cytochrome P450 oxidoreductase (POR), was inactive (desirable prodrug attribute) as an inhibitor of tubulin polymerization (IC50 > 20 µM), and demonstrated hypoxia-selective activation in the A549 cell line [hypoxia cytotoxicity ratio (HCR) = 41.5]. The related CA1-gem-dimethylnitrothiophene BAPC 41 was also promising (HCR = 12.5) with complete cleavage (90 min) upon treatment with POR. In a preliminary in vivo dynamic bioluminescence imaging study, BAPC 45 (180 mg/kg, ip) induced a decrease (within 4 h) in light emission in a 4T1 syngeneic mouse breast tumor model, implying activation and vascular disruption.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Pró-Fármacos/farmacologia , Estilbenos/farmacologia , Células A549 , Animais , Antineoplásicos Fitogênicos/química , Neoplasias da Mama/tratamento farmacológico , Hipóxia Celular , Colchicina/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , NADPH-Ferri-Hemoproteína Redutase/química , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Pró-Fármacos/química , Estilbenos/química , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo
2.
Medchemcomm ; 10(8): 1445-1456, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31534659

RESUMO

Numerous members of the combretastatin and chalcone families of natural products function as inhibitors of tubulin polymerization through a binding interaction at the colchicine site on ß-tubulin. These molecular scaffolds inspired the development of many structurally modified derivatives and analogues as promising anticancer agents. A productive design blueprint that involved molecular hybridization of the pharmacophore moieties of combretastatin A-4 (CA4) and the chalcones led to the discovery of two promising lead molecules referred to as KGP413 and SD400. The corresponding water-soluble phosphate prodrug salts of KGP413 and SD400 selectively damaged tumor-associated vasculature, thus highlighting the potential development of these molecules as vascular disrupting agents (VDAs). These previous studies prompted our current investigation of conformationally restricted chalcones. Herein, we report the synthesis of cyclic chalcones and related analogues that incorporate structural motifs of CA4, and evaluation of their cytotoxicity against human cancer cell lines [NCI-H460 (lung), DU-145 (prostate), and SK-OV-3 (ovarian)]. While these molecules proved inactive as inhibitors of tubulin polymerization (IC50 > 20 µM), eight molecules demonstrated good antiproliferative activity (GI50 < 20 µM) against all three cancer cell lines, and compounds 2j and 2l demonstrated sub-micromolar cytotoxicity. To the best of our knowledge these molecules represent the most potent (based on GI50) cyclic chalcones known to date, and are promising lead molecules for continued investigation.

3.
J Med Chem ; 62(11): 5594-5615, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31059248

RESUMO

A promising design paradigm for small-molecule inhibitors of tubulin polymerization that bind to the colchicine site draws structural inspiration from the natural products colchicine and combretastatin A-4 (CA4). Our previous studies with benzocycloalkenyl and heteroaromatic ring systems yielded promising inhibitors with dihydronaphthalene and benzosuberene analogues featuring phenolic (KGP03 and KGP18) and aniline (KGP05 and KGP156) congeners emerging as lead agents. These molecules demonstrated dual mechanism of action, functioning both as potent vascular disrupting agents (VDAs) and as highly cytotoxic anticancer agents. A further series of analogues was designed to extend functional group diversity and investigate regioisomeric tolerance. Ten new molecules were effective inhibitors of tubulin polymerization (IC50 < 5 µM) with seven of these exhibiting highly potent activity comparable to CA4, KGP18, and KGP03. For one of the most effective agents, dose-dependent vascular shutdown was demonstrated using dynamic bioluminescence imaging in a human prostate tumor xenograft growing in a rat.


Assuntos
Cumarínicos/química , Cumarínicos/farmacologia , Desenho de Fármacos , Multimerização Proteica/efeitos dos fármacos , Tubulina (Proteína)/química , Animais , Linhagem Celular Tumoral , Técnicas de Química Sintética , Cumarínicos/síntese química , Humanos , Masculino , Estrutura Quaternária de Proteína , Ratos
4.
Medchemcomm ; 9(10): 1649-1662, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429970

RESUMO

The natural products colchicine and combretastatin A-4 (CA4) have provided inspiration for the discovery and development of a wide array of derivatives and analogues that inhibit tubulin polymerization through a binding interaction at the colchicine site on ß-tubulin. A water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) has demonstrated the ability to selectively damage tumor-associated vasculature and ushered in a new class of developmental anticancer agents known as vascular disrupting agents (VDAs). Through a long-term program of structure activity relationship (SAR) driven inquiry, we discovered that the dihydronaphthalene molecular scaffold provided access to small-molecule inhibitors of tubulin polymerization. In particular, a dihydronaphthalene analogue bearing a pendant trimethoxy aryl ring (referred to as KGP03) and a similar aroyl ring (referred to as KGP413) were potent inhibitors of tubulin polymerization (IC50 = 1.0 and 1.2 µM, respectively) and displayed low nM cytotoxicity against human cancer cell lines. In order to enhance water-solubility for in vivo evaluation, the corresponding phosphate prodrug salts (KGP04 and KGP152, respectively) were synthesized. In a preliminary in vivo study in a SCID-BALB/c mouse model bearing the human breast tumor MDA-MB-231-luc, a 99% reduction in signal was observed with bioluminescence imaging (BLI) 4 h after IP administration of KGP152 (200 mg kg-1) indicating reduced tumor blood flow. In a separate study, disruption of tumor-associated blood flow in a Fischer rat bearing an A549-luc human lung tumor was observed by color Doppler ultrasound following administration of KGP04 (15 mg kg-1).

5.
Bioorg Med Chem Lett ; 27(5): 1304-1310, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28117205

RESUMO

The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC50 value of 202nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC50=189nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94.


Assuntos
Catepsina L/antagonistas & inibidores , Organofosfatos/química , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/farmacologia , Tioureia/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Pró-Fármacos/química , Sais/síntese química , Sais/farmacologia , Solubilidade , Tiossemicarbazonas/química , Tioureia/síntese química , Tioureia/química , Tioureia/farmacologia , Água/química
6.
Bioorg Med Chem ; 24(5): 938-956, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26852340

RESUMO

Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodrug conjugates (AAPCs) of potent amino combretastatin, amino dihydronaphthalene, and amino benzosuberene analogs were synthesized along with their corresponding water-soluble hydrochloride salts. These compounds were evaluated for their ability to inhibit tubulin polymerization and for their cytotoxicity against selected human cancer cell lines. The amino-based parent anticancer agents 7, 8, 32 (also referred to as KGP05) and 33 (also referred to as KGP156) demonstrated potent cytotoxicity (GI50=0.11-40nM) across all evaluated cell lines, and they were strong inhibitors of tubulin polymerization (IC50=0.62-1.5µM). The various prodrug conjugates and their corresponding salts were investigated for cleavage by the enzyme leucine aminopeptidase (LAP). Four of the glycine water-soluble AAPCs (16, 18, 44 and 45) showed quantitative cleavage by LAP, resulting in the release of the highly cytotoxic parent drug, whereas partial cleavage (<10-90%) was observed for other prodrugs (15, 17, 24, 38 and 39). Eight of the nineteen AAPCs (13-16, 42-45) showed significant cytotoxicity against selected human cancer cell lines. The previously reported CA1-diamine analog and its corresponding hydrochloride salt (8 and 10, respectively) caused extensive disruption (at a concentration of 1.0µM) of human umbilical vein endothelial cells growing in a two-dimensional tubular network on matrigel. In addition, compound 10 exhibited pronounced reduction in bioluminescence (greater than 95% compared to saline control) in a tumor bearing (MDA-MB-231-luc) SCID mouse model 2h post treatment (80mg/kg), with similar results observed upon treatment (15mg/kg) with the glycine amino-dihydronaphthalene AAPC (compound 44). Collectively, these results support the further pre-clinical development of the most active members of this structurally diverse collection of water-soluble prodrugs as promising anticancer agents functioning through a mechanism involving vascular disruption.


Assuntos
Antineoplásicos/uso terapêutico , Bibenzilas/uso terapêutico , Cumarínicos/uso terapêutico , Naftalenos/uso terapêutico , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Aminoácidos/química , Aminoácidos/uso terapêutico , Animais , Antineoplásicos/química , Bibenzilas/química , Mama/irrigação sanguínea , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cumarínicos/química , Desenho de Fármacos , Feminino , Humanos , Camundongos , Camundongos SCID , Naftalenos/química , Neoplasias/patologia , Imagem Óptica , Pró-Fármacos/química , Solubilidade , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Água/química
7.
Medchemcomm ; 7(12): 2418-2427, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28217276

RESUMO

The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs). Combination of salient structural features associated with colchicine and CA4 led to the design and synthesis of a variety of fused aryl-cycloalkyl and aryl-heterocyclic compounds that function as inhibitors of tubulin polymerization. Prominent among these compounds is a benzosuberene analogue (referred to as KGP18), which demonstrates sub-nM cytotoxicity against human cancer cell lines and functions (when administered as a water-soluble prodrug salt) as a VDA in mouse models. Structure activity relationship considerations led to the evaluation of benzocyclooctyl [6,8 fused] and indene [6,5 fused] ring systems. Four benzocyclooctene and four indene analogues were prepared and evaluated biologically. Three of the benzocyclooctene analogues were active as inhibitors of tubulin polymerization (IC50 < 5 µM), and benzocyclooctene phenol 23 was comparable to KGP18 in terms of potency. The analogous indene-based compound 31 also functioned as an inhibitor of tubulin polymerization (IC50 = 11 µM) with reduced potency. The most potent inhibitor of tubulin polymerization from this group was benzocyclooctene analogue 23, and it was converted to its water-soluble prodrug salt 24 to assess its potential as a VDA. Preliminary in vivo studies, which utilized the MCF7-luc-GFP-mCherry breast tumor in a SCID mouse model, demonstrated that treatment with 24 (120 mg/kg) resulted in significant vascular shutdown, as evidenced by bioluminescence imaging at 4 h post administration, and that the effect continued at both 24 and 48 h. Contemporaneous studies with CA4P, a clinically relevant VDA, were carried out as a positive control.

8.
Bioorg Med Chem ; 23(21): 6974-92, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26462052

RESUMO

Upregulation of cathepsin L in a variety of tumors and its ability to promote cancer cell invasion and migration through degradation of the extracellular matrix suggest that cathepsin L is a promising biological target for the development of anti-metastatic agents. Based on encouraging results from studies on benzophenone thiosemicarbazone cathepsin inhibitors, a series of fourteen benzoylbenzophenone thiosemicarbazone analogues were designed, synthesized, and evaluated for their inhibitory activity against cathepsins L and B. Thiosemicarbazone inhibitors 3-benzoylbenzophenone thiosemicarbazone 1, 1,3-bis(4-fluorobenzoyl)benzene thiosemicarbazone 8, and 1,3-bis(2-fluorobenzoyl)-5-bromobenzene thiosemicarbazone 32 displayed the greatest potency against cathepsin L with low IC50 values of 9.9 nM, 14.4 nM, and 8.1 nM, respectively. The benzoylbenzophenone thiosemicarbazone analogues evaluated were selective in their inhibition of cathepsin L compared to cathepsin B. Thiosemicarbazone analogue 32 inhibited invasion through Matrigel of MDA-MB-231 breast cancer cells by 70% at 10 µM. Thiosemicarbazone analogue 8 significantly inhibited the invasive potential of PC-3ML prostate cancer cells by 92% at 5 µM. The most active cathepsin L inhibitors from this benzoylbenzophenone thiosemicarbazone series (1, 8, and 32) displayed low cytotoxicity toward normal primary cells [in this case human umbilical vein endothelial cells (HUVECs)]. In an initial in vivo study, 3-benzoylbenzophenone thiosemicarbazone (1) was well-tolerated in a CDF1 mouse model bearing an implanted C3H mammary carcinoma, and showed efficacy in tumor growth delay. Low cytotoxicity, inhibition of cell invasion, and in vivo tolerability are desirable characteristics for anti-metastatic agents functioning through an inhibition of cathepsin L. Active members of this structurally diverse group of benzoylbenzophenone thiosemicarbazone cathepsin L inhibitors show promise as potential anti-metastatic, pre-clinical drug candidates.


Assuntos
Antineoplásicos/síntese química , Catepsina L/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Tiossemicarbazonas/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzofenonas/química , Sítios de Ligação , Catepsina B/antagonistas & inibidores , Catepsina B/metabolismo , Catepsina L/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Cisteína Proteinase/uso terapêutico , Desenho de Fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração Inibidora 50 , Isomerismo , Cinética , Neoplasias Mamárias Animais/tratamento farmacológico , Camundongos , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/uso terapêutico , Transplante Heterólogo
9.
Cancer Lett ; 369(1): 229-41, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26325604

RESUMO

This study describes the vascular disrupting ability and the mechanism of action of the indole-based tubulin-binding compound, OXi8006, and its water-soluble phosphate prodrug OXi8007. Treatment of rapidly proliferating human umbilical vein endothelial cells (HUVECs), used as a model for the tumor vasculature, with OXi8006 or OXi8007, caused potent microtubule disruption followed by extensive reorganization of the cytoskeletal network. The mechanism of action involved an increase in focal adhesion formation associated with an increase in phosphorylation of both non-muscle myosin light chain and focal adhesion kinase. These effects were dramatically diminished by an inhibitor of RhoA kinase, a downstream effector of RhoA. Cell cycle blockade at G2/M and cytotoxicity toward rapidly proliferating HUVECs were also observed. Capillary-like networks of HUVECs were disrupted by the action of both OXi8006 and OXi8007. The prodrug OXi8007 exhibited potent and rapid dose-dependent antivascular activity assessed by dynamic bioluminescence imaging (BLI) in an MDA-MB-231-luc breast cancer xenograft mouse model. By 6 hours post treatment, over 93% of the BLI signal was abolished with only a slight recovery at 24 hours. These findings were confirmed by histology. The results from this study demonstrate that OXi8007 is a potent vascular disrupting agent acting through an anti-microtubule mechanism involving RhoA.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Indóis/farmacologia , Animais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/irrigação sanguínea , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/patologia , Feminino , Adesões Focais/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Indóis/uso terapêutico , Camundongos SCID , Fosforilação , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Bioorg Med Chem ; 23(24): 7497-520, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26775540

RESUMO

The discovery of 3-methoxy-9-(30,40,50-trimethoxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-4-ol (a benzosuberene-based analogue referred to as KGP18) was originally inspired by the natural products colchicine and combretastatin A-4 (CA4). The relative structural simplicity and ease of synthesis of KGP18, coupled with its potent biological activity as an inhibitor of tubulin polymerization and its cytotoxicity (in vitro) against human cancer cell lines, has resulted in studies focused on new analogue design and synthesis. Our goal was to probe the relationship of structure to function in this class of anticancer agents. A series of twenty-two new benzosuberene-based analogues of KGP18 was designed and synthesized. These compounds vary in their methoxylation pattern and separately incorporate trifluoromethyl groups around the pendant aryl ring for the evaluation of the effect of functional group modifications on the fused six-membered aromatic ring. In addition, the 8,9-saturated congener of KGP18 has been synthesized to assess the necessity of unsaturation at the carbon atom bearing the pendant aryl ring. Six of the molecules from this benzosuberene-series of compounds were active (IC50 < 5 lM) as inhibitors of tubulin polymerization while four analogues were comparable (IC50 approximately 1 lM) in their tubulin inhibitory activity to CA4 and KGP18. The potency of a bis-trifluoromethyl analogue 74 and the unsaturated KGP18 derivative 73 as inhibitors of tubulin assembly along with their moderate cytotoxicity suggested the potential utility of these compounds as vascular disrupting agents (VDAs) to selectively target microvessels feeding tumors. Accordingly, water-soluble and DMSO-soluble phosphate prodrug salts of each were synthesized for preliminary in vivo studies to assess their potential efficacy as VDAs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cumarínicos/uso terapêutico , Humanos , Camundongos SCID , Simulação de Acoplamento Molecular , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Polimerização/efeitos dos fármacos , Moduladores de Tubulina/uso terapêutico
11.
Bioorg Med Chem ; 21(24): 8019-32, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24183586

RESUMO

Diversely functionalized, fused aryl-alkyl ring systems hold a prominent position as well-established molecular frameworks for a variety of anti-cancer agents. The benzosuberene (6,7 fused, also referred to as dihydro-5H-benzo[7]annulene and benzocycloheptene) ring system has emerged as a valuable molecular core component for the development of inhibitors of tubulin assembly, which function as antiproliferative anti-cancer agents and, in certain cases, as vascular disrupting agents (VDAs). Both a phenolic-based analogue (known as KGP18, compound 39) and its corresponding amine-based congener (referred to as KGP156, compound 45), which demonstrate strong inhibition of tubulin assembly (low micromolar range) and potent cytotoxicity (picomolar range for KGP18 and nanomolar range for KGP156) are noteworthy examples of such benzosuberene-based compounds. In order to extend the structure-activity relationship (SAR) knowledge base related to benzosuberene anti-cancer agents, a series of eleven analogues (including KGP18) were prepared in which the methoxylation pattern on the pendant aryl ring as well as functional group incorporation on the fused aryl ring were varied. The synthetic approach to these compounds featured a sequential Wittig olefination, reduction, Eaton's reagent-mediated cyclization strategy to achieve the core benzosuberone intermediate, and represented a higher-yielding synthesis of KGP18 (which we prepared previously through a ring-expansion strategy). Incorporation of a fluorine or chlorine atom at the 1-position of the fused aryl ring or replacement of one of the methoxy groups with hydrogen (on the pendant aryl ring of KGP18) led to benzosuberene analogues that were both strongly inhibitory against tubulin assembly (IC50 approximately 1.0 µM) and strongly cytotoxic against selected human cancer cell lines (for example, GI50=5.47 nM against NCI-H460 cells with fluoro-benzosuberene analogue 37). A water-soluble phosphate prodrug salt of KGP18 (referred to as KGP265, compound 44) and a water-soluble serinamide salt (compound 48) of KGP156 were also synthesized and evaluated in this study.


Assuntos
Antineoplásicos/farmacologia , Benzocicloeptenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzocicloeptenos/síntese química , Benzocicloeptenos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo
12.
J Nat Prod ; 76(9): 1668-78, 2013 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-24016002

RESUMO

The natural products colchicine and combretastatin A-4 are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI50 = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC50 = 1.1 µM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent that may prove useful for the treatment of cancer.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Bibenzilas/farmacologia , Indóis/síntese química , Indóis/farmacologia , Organofosfatos/síntese química , Organofosfatos/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/química , Bibenzilas/química , Colchicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/química , Concentração Inibidora 50 , Masculino , Camundongos , Estrutura Molecular , Organofosfatos/química , Pró-Fármacos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Estilbenos , Relação Estrutura-Atividade , Tubulina (Proteína)/efeitos dos fármacos
13.
Bioorg Med Chem ; 21(21): 6831-43, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23993969

RESUMO

The discovery of a 2-aryl-3-aroyl indole-based small-molecule inhibitor of tubulin assembly (referred to as OXi8006) inspired the design, synthesis, and biological evaluation of a series of diversely functionalized analogues. In the majority of examples, the pendant 2-aryl ring contained a 3-hydroxy-4-methoxy substitution pattern, and the fused aryl ring featured a 6-methoxy group. Most of the variability was in the 3-aroyl moiety, which was modified to incorporate methoxy (33-36), nitro (25-27), halogen (28-29), trifluoromethyl (30), or trifluoromethoxy (31-32) functionalities. In two analogues (34 and 36), the methoxy substitution pattern in the fused aryl ring varied, while in another derivative (35) the phenolic moiety was translocated from the pendant 2-aryl ring to position-7 of the fused aryl ring. Each of the compounds were evaluated for their cytotoxicity (in vitro) against the SK-OV-3 (ovarian), NCI-H460 (lung), and DU-145 (prostate) human cancer cell lines and for their ability to inhibit tubulin assembly. Four of the compounds (30, 31, 35, 36) proved to be potent inhibitors of tubulin assembly (IC50 <5µM), and three of these compounds (31, 35, 36) were strongly cytotoxic against the three cancer cell lines. The most active compound (36) in this series, which incorporated a methoxy group at position-7, was comparable in terms of inhibition of tubulin assembly and cytotoxicity to the lead compound OXi8006.


Assuntos
Antineoplásicos/síntese química , Indóis/química , Indóis/síntese química , Moduladores de Tubulina/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colchicina/química , Colchicina/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/metabolismo , Indóis/toxicidade , Ligação Proteica , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/toxicidade
14.
Eur J Med Chem ; 58: 568-72, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23168380

RESUMO

Kinetic analysis of the mode of inhibition of cathepsin L by KGP94, a lead compound from a privileged library of functionalized benzophenone thiosemicarbazone derivatives, demonstrated that it is a time-dependent, reversible, and competitive inhibitor of the enzyme. These results are consistent with the formation of a transient covalent bond, and are supported by molecular modeling that places the thiocarbonyl of the inhibitor in proximity to the thiolate moiety of the enzyme active site Cys25. KGP94 significantly decreased the activity of cathepsin L toward human type I collagen, and impeded both migration and invasion of MDA-MB-231 human breast cancer cells. Growth retardation was achieved in vivo against both recently implanted and established tumours using a C3H mouse mammary carcinoma model.


Assuntos
Antineoplásicos/farmacologia , Catepsina L/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Tiossemicarbazonas/farmacologia , Tioureia/análogos & derivados , Animais , Antineoplásicos/química , Catepsina L/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Cisteína Proteinase/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/química , Tioureia/química , Tioureia/farmacologia
15.
Medchemcomm ; 3(6): 720-724, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23772309

RESUMO

The recent discovery of a small-molecule benzosuberene-based phenol that demonstrates remarkable picomolar cytotoxicity against selected human cancer cell lines and strongly inhibits tubulin polymerization (1-2 µM) inspired the design and synthesis of a variety of new, structurally diverse benzosuberene derivatives. An efficient synthetic route to functionalized benzosuberenes was developed. This methodology utilized a Wittig reaction, followed by a selective alkene reduction and ring-closing cyclization to form the core benzosuberone structure. This synthetic route facilitated the preparation of a 6-nitro-1-(3',4',5'-trimethoxyphenyl) benzosuberene derivative and its corresponding 6-amino analogue in good yield. The 6-amino analogue was a strong inhibitor of tubulin polymerization (1.2 µM), demonstrated enhanced cytotoxicity against the human cancer cell lines examined (GI50 = 33 pM against SK-OV-3 ovarian cancer, for example), and exhibited a concentration dependent disruption of a pre-established capillary-like network of tubules formed from human umbilical vein endothelial cells.

16.
J Nat Prod ; 74(7): 1568-74, 2011 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-21718055

RESUMO

The natural products combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent cancer vascular disrupting agents and inhibitors of tubulin assembly (IC50 = 1-2 µM). The phosphorylated prodrugs CA4P and CA1P are undergoing human clinical trials against cancer. CA1 is unique due to its incorporation of a vicinal phenol, which has afforded the opportunity to prepare both diphosphate and regioisomeric monophosphate derivatives. Here, we describe the first synthetic routes suitable for the regiospecific preparation of the CA1-monophosphates CA1MPA (8a/b) and CA1MPB (4a/b). The essential regiochemistry necessary to distinguish between the two vicinal phenolic groups was accomplished with a tosyl protecting group strategy. Each of the four monophosphate analogues (including Z and E isomers) demonstrated in vitro cytotoxicity against selected human cancer cell lines comparable to their corresponding diphosphate congeners. Furthermore, Z-CA1MPA (8a) and Z-CA1MPB (4a) were inactive as inhibitors of tubulin assembly (IC50 > 40 µM), as anticipated in this pure protein assay.


Assuntos
Antineoplásicos Fitogênicos/síntese química , Estilbenos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Solubilidade , Estereoisomerismo , Estilbenos/farmacologia , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Água
17.
Bioorg Med Chem Lett ; 20(22): 6610-5, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20933415

RESUMO

A series of thiosemicarbazone analogs based on the benzophenone, thiophene, pyridine, and fluorene molecular frameworks has been prepared by chemical synthesis and evaluated as small-molecule inhibitors of the cysteine proteases cathepsin L and cathepsin B. The two most potent inhibitors of cathepsin L in this series (IC(50)<135 nM) are brominated-benzophenone thiosemicarbazone analogs that are further functionalized with a phenolic moiety (2 and 6). In addition, a bromo-benzophenone thiosemicarbazone acetyl derivative (3) is also strongly inhibitory against cathepsin L (IC(50)=150.8 nM). Bromine substitution in the thiophene series results in compounds that demonstrate only moderate inhibition of cathepsin L. The two most active analogs in the benzophenone thiosemicarbazone series are highly selective for their inhibition of cathepsin L versus cathepsin B.


Assuntos
Benzofenonas/química , Catepsina L/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Fluorenos/química , Piridinas/química , Tiofenos/química , Tiossemicarbazonas/farmacologia , Inibidores de Cisteína Proteinase/química , Tiossemicarbazonas/química
18.
J Nat Prod ; 73(6): 1093-101, 2010 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-20496923

RESUMO

Synthetic routes have been established for the preparation of regio- and stereoisomerically pure samples of the mono-beta-d-glucuronic acid derivatives of combretastatin A-1, referred to as CA1G1 (5a) and CA1G2 (6a). Judicious choice of protecting groups for the catechol ring was required for the regiospecific introduction of the glucuronic acid moiety. The tosyl group proved advantageous in this regard. The two monoglucuronic acid analogues demonstrate low cytotoxicity (compared to CA1, 2) against selected human cancer cell lines, with CA1G1 being slightly more potent than CA1G2.


Assuntos
Antineoplásicos Fitogênicos/síntese química , Ácido Glucurônico/química , Ácido Glucurônico/síntese química , Estilbenos/química , Estilbenos/síntese química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Glucurônico/farmacologia , Humanos , Estrutura Molecular , Estereoisomerismo , Estilbenos/farmacologia
19.
Bioorg Med Chem Lett ; 20(4): 1415-9, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20089402

RESUMO

A small library of 36 functionalized benzophenone thiosemicarbazone analogs has been prepared by chemical synthesis and evaluated for their ability to inhibit the cysteine proteases cathepsin L and cathepsin B. Inhibitors of cathepsins L and B have the potential to limit or arrest cancer metastasis. The six most active inhibitors of cathepsin L (IC50<85 nM) in this series incorporate a meta-bromo substituent in one aryl ring along with a variety of functional groups in the second aryl ring. These six analogs are selective for their inhibition of cathepsin L versus cathepsin B (IC50>10,000 nM). The most active analog in the series, 3-bromophenyl-2'-fluorophenyl thiosemicarbazone 1, also efficiently inhibits cell invasion of the DU-145 human prostate cancer cell line.


Assuntos
Catepsina B/antagonistas & inibidores , Catepsina L/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Desenho de Fármacos , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/farmacologia , Domínio Catalítico , Inibidores de Cisteína Proteinase/química , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Tiossemicarbazonas/química
20.
Bioorg Med Chem ; 17(19): 6993-7001, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19733085

RESUMO

Structural redesign of selected non-steroidal estrogen receptor binding compounds has previously been successful in the discovery of new inhibitors of tubulin assembly. Accordingly, tetra-substituted alkene analogues (21-30) were designed based in part on combinations of the structural and electronic components of tamoxifen and combretastatin A-4 (CA4). The McMurry coupling reaction was used as the key synthetic step in the preparation of these tri- and tetra-arylethylene analogues. The structural assignment of E, Z isomers was determined on the basis of 2D-NOESY experiments. The ability of these compounds to inhibit tubulin polymerization and cell growth in selected human cancer cell lines was evaluated. Although the compounds were found to be less potent than CA4, these analogues significantly advance the known structure-activity relationship associated with the colchicine binding site on beta-tubulin.


Assuntos
Antineoplásicos/síntese química , Etilenos/síntese química , Hidrocarbonetos Aromáticos/síntese química , Moduladores de Tubulina/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina , Desenho de Fármacos , Etilenos/farmacologia , Humanos , Hidrocarbonetos Aromáticos/farmacologia , Fenômenos de Química Orgânica , Receptores de Estrogênio/metabolismo , Relação Estrutura-Atividade , Moduladores de Tubulina/farmacologia
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