ABSTRACT
BACKGROUND: Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian population. METHODS: Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHRmut, including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy. RESULTS: Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0-43.7), the median overall survival (OS) was not significantly different among patients with gHRmut, non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHRmut. Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7-33.7) versus 9.6 months (95% CI 5.9-17.6), P = 0.001. However, the median OS of patients without gHRmut was 14.5 months (95% CI 13.2-16.9) and 12.6 months (95% CI 10.8-14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis. CONCLUSIONS: Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHRmut patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis.
Subject(s)
Germ-Line Mutation , Pancreatic Neoplasms , Humans , Taiwan , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Homologous Recombination , Genes, BRCA2 , BRCA1 Protein/genetics , BRCA2 Protein/geneticsABSTRACT
Salvinal is a natural lignan isolated from the roots of Salvia mitorrhiza Bunge (Danshen). Previous studies have demonstrated its anti-proliferative activity in both drug-sensitive and -resistant cancer cell lines, with IC50 values ranging from 4-17 µM. In this study, a series of salvinal derivatives was synthesized and evaluated for the structure-activity relationship. Among the twenty-four salvinal derivatives, six compounds showed better anticancer activity than salvinal. Compound 25 displayed excellent anticancer activity, with IC50 values of 0.13-0.14 µM against KB, KB-Vin10 (overexpress MDR/Pgp), and KB-7D (overexpress MRP) human carcinoma cell lines. Based on our in vitro microtubule depolymerization assay, compound 25 showed depolymerization activity in a dose-dependent manner. Our findings indicate that compound 25 is a promising anticancer agent with depolymerization activity that has potential for the management of malignance.
Subject(s)
Antineoplastic Agents , Humans , Drug Screening Assays, Antitumor , Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Tubulin Modulators/pharmacology , Microtubules , Cell Proliferation , Dose-Response Relationship, Drug , Molecular Structure , Cell Line, Tumor , Molecular Docking SimulationABSTRACT
We report structure-activity relationships of 1-arylsulfonyl indoline based benzamides. The benzamide (9) exhibits striking tubulin inhibition with an IC50 value of 1.1⯵M, better than that of combretastain A-4 (3), and substantial antiproliferative activity against a variety of cancer cells, including MDR-positive cell lines with an IC50 value of 49â¯nMâ¯(KB), 79â¯nM (A549), 63â¯nM (MKN45), 64â¯nM (KB-VIN10), 43â¯nM (KB-S15), and 46â¯nM (KB-7D). Dual inhibitory potential of compound 9 was found as it demonstrated significant inhibitory potential against HDAC1, 2 and 6 in comparison to MS-275 (6). Some key interactions of 9 with the amino acid residues of the active site of tubulin and with amino acid residues of HDAC 1 isoform have been figured out by molecular modeling. Compound 9 also demonstrated significant in vivo efficacy in the human non-small cell lung cancer A549 xenograft model as well as B-cell lymphoma BJAB xenograft tumor model.
Subject(s)
Histone Deacetylase Inhibitors/pharmacology , Indoles/pharmacology , A549 Cells , Animals , Antineoplastic Agents/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Catalytic Domain , Cell Line, Tumor , Cell Proliferation/drug effects , Heterografts , Humans , Indoles/chemistry , Lymphoma, B-Cell/drug therapy , Mice , Models, Molecular , Protein Binding , Tubulin Modulators/pharmacologyABSTRACT
MEC-17, a newly identified alpha-tubulin-N-acetyltransferase 1, serves as the major α-tubulin acetyltransferase to promote α-tubulin acetylation in vitro and in vivo. Alteration of α-tubulin acetylation may be involved in morphology regulation, cell migration, and tumour metastasis. However, MEC-17's role in cell physiology and its effect on epithelial-mesenchymal transition (EMT) and cell polarity remain elusive. In the present study, we characterized the overexpressed or downregulated cell models through gene targeting as MEC-17 gain- or loss-of-function. Overexpression of MEC-17 enhanced the cell spreading area, suppressed pseudopods formation in a three-dimensional (3D) culture system, and inhibited cancer cell migratory and invasive ability and tumour metastasis by orthotopic lung cancer animal model. Furthermore, morphological change and migration inhibition of cancer cells were accompanied by EMT repression, Golgi reorientation, and polarity disruption caused by alteration of cdc42 activity via a decrease in Rho-GAP, ARHGAP21. By contrast, a reduction in endogenous MEC-17 accelerated the pseudopods formation and EMT, and facilitated cell migration and invasion. These results demonstrated the crucial role of MEC-17 in the modulation of intrinsic cell morphogenesis, migration, and invasive function through regulation of EMT and cell polarity.
Subject(s)
Acetyltransferases/metabolism , Cell Polarity , Epithelial-Mesenchymal Transition , A549 Cells , Acetylation , Cell Movement , Humans , Neoplasm Invasiveness , Neoplasm Metastasis , Pseudopodia/metabolism , Tubulin/metabolismABSTRACT
This study reports the synthesis of a series of heteroaroyl-2-hydroxy-3,4,5-trimethoxybenzenes, which are potent antitubulin agents. Compound 13, (2-hydroxy-3,4,5-trimethoxyphenyl)-(6-methoxy-1H-indol-3-yl)-methanone exhibits marked antiproliferative activity against KB and MKN45 cells with IC50 values of 8.8 and 10.5 nM, respectively, binds strongly to the colchicine binding site and leads to inhibition of tubulin polymerization. It also behaves as a vascular disrupting agent which suppresses the formation of capillaries. The C2-OH group in the A-ring of this compound not only retains the biological activity but has valuable physicochemical properties.
Subject(s)
Antimitotic Agents/chemistry , Antimitotic Agents/pharmacology , Drug Evaluation, Preclinical/methods , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Antimitotic Agents/metabolism , Benzene/chemistry , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Colchicine/metabolism , Drug Resistance, Neoplasm/drug effects , HT29 Cells/drug effects , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship , Tubulin Modulators/chemistry , Tubulin Modulators/metabolism , Tubulin Modulators/pharmacologyABSTRACT
Pangolins are considered difficult to maintain in zoos, often attributed to problems in feeding management. Taipei Zoo's designation as a wildlife rescue center for Chinese pangolins (Manis pentadactyla) has resulted in long term feeding experience with development of diets that support recovery, maintenance, and reproduction, as well as experimental opportunities to further understand digestive physiology to optimize nutrition. Opportunistic dissection of 10 animals revealed details of the tongue, salivary glands, stomach and gastrointestinal tract (GIT), including confirmation of anatomical differences between Asian and African pangolin species. Length of the total GIT relative to body length (â¼ 9:1) was greater than found in domestic carnivores, more similar to omnivorous species. Intake and digestion trials conducted with 4 animals demonstrated that pangolins maintained body weights (BW; 6-9 kg) consuming diets containing 32-40% crude protein, 20-25% crude fat, and 13-28% crude fiber (DM basis). Daily DM intakes ranged from â¼40 to 70 g per animal, with digestible energy intake 51.5-87.5 kcal /kg BW(0.75) /day; pangolins consumed 9.4-15.2 g DM/kg BW(0.75) /day. Dietary energy data support observations of low metabolism and maintenance requirements for this species, similar to values reported for other myrmecophageous species. Addition of 5% ground chitin to diets improved fecal consistency, and decreased digestibility of DM, protein, and energy; addition of chitosan (chitin treated with NaOH) resulted in diet rejection. This information may assist in enhancement of captive diets, as well as in controlling obesity in pangolins.
Subject(s)
Animals, Zoo/anatomy & histology , Animals, Zoo/physiology , Digestive System/anatomy & histology , Eating/physiology , Mammals/anatomy & histology , Mammals/physiology , Animal Nutritional Physiological Phenomena , Animals , Digestion , TaiwanABSTRACT
Described herein is the development of a novel series of 7-anilino-indoline-N-benzenesulfonamides, derived from ABT751 (1), as potent anticancer agents. Amongst the synthesized series, compounds 6, 12, 13, and 14 have shown comparable to better anticancer activity on comparing with compound 1. 7-(4-Cyanophenylamino)-1-(4-methoxybenzenesulfonyl)indoline (13) was found to be the most potent one with up to 6 fold better activity against KB, HT29, and MKN45 cancer cell lines with IC50 values of 49.7, 149, and 92nM, respectively. Compound 13 was also found inhibiting multidrug resistant cancer cell lines, blocking cell cycle at G2/M phase, and inhibiting tubulin polymerization. Capillary disruption assay results revealed that compound 13 was able to disrupt formed capillaries in a concentration-dependent manner without affecting cell viability.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Capillaries/drug effects , Indoles/pharmacology , Mitosis/drug effects , Sulfonamides/pharmacology , Tubulin Modulators/pharmacology , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HT29 Cells , Humans , Indoles/chemical synthesis , Indoles/chemistry , KB Cells , Molecular Structure , Polymerization/drug effects , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Tubulin/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistryABSTRACT
A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC50 value of 0.1 µM. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1 and 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, N-hydroxy-N'-phenyloctanediamide) and is therefore seen as a suitable candidate for further investigation.
Subject(s)
Antineoplastic Agents/chemical synthesis , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylases/metabolism , Sulfonamides/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Female , HCT116 Cells , HEK293 Cells , Histone Deacetylase 6 , Histone Deacetylase Inhibitors/pharmacokinetics , Histone Deacetylase Inhibitors/pharmacology , Humans , Mice , Mice, Inbred ICR , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
2-Hydroxy-3,4,5-trimethoxybenzophenones (8-16) manifest pseudo-ring formation involving intramolecular hydrogen bonding of the 2-OH and the carbonyl group. Among the synthetic products described in this report, (3-hydroxy-4-methoxyphenyl)(2-hydroxy-3,4,5-trimethoxyphenyl)-methanone (14) and (3-amino-4-methoxyphenyl)(2-hydroxy-3,4,5-trimethoxy-phenyl)methanone (16) exhibit significant antiproliferative activity against KB cells with IC50 values of 11.1 and 11.3 nM, respectively. These two compounds also displayed tubulin affinity comparable to that of combretastatin A-4. In studies with human umbilical vein endothelial cells, compounds 14 and 16 revealed concentration-dependent vascular-disrupting properties. The results support the rationale of the pseudo-ring concept and suggest further investigation of A-ring modification in these benzophenones.
Subject(s)
Antimitotic Agents/pharmacology , Benzophenones/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Antimitotic Agents/chemical synthesis , Antimitotic Agents/chemistry , Benzophenones/chemical synthesis , Benzophenones/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/antagonists & inhibitors , Dose-Response Relationship, Drug , HT29 Cells , Humans , KB Cells , Molecular Structure , Polymerization/drug effects , Structure-Activity Relationship , Tubulin/metabolismABSTRACT
Preliminary biological data on 7-anilino-6-azaindoles (8-11) suggested that hydrophobic substituents at C7 contribute to enhancement of antiproliferative activity. A novel series of 7-aryl-6-azaindole-1-benzenesulfonamides (12-22) were developed and showed improved cytotoxicity compared to ABT751 (5). The conversion of C7 phenyl rings into C7 heterocycles led to a remarkable improvement of antiproliferative activity. Among all the synthetic products, 7-(2-furanyl)-1-(4-methoxybenzenesulfonyl)-6-azaindole (21) exhibited the most potent anticancer activity against KB, HT29, MKN45, and H460 cancer cell lines with IC50 values of 21.1, 32.0, 27.5, and 40.0 nM, respectively. Bioassays indicated that 21 not only inhibits tubulin polymerization by binding to tubulin at the colchicine binding site but also arrests the cell cycle at the G2/M phase with slight arrest at the sub-G1 phase. Compound 21 also functions as a vascular disrupting agent and dose-dependently inhibits tumor growth without significant change of body weight in an HT29 xenograft mouse model. Taken together, compound 21 has potential for further development as a novel class of anticancer agents.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , Indoles/pharmacology , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Design , Female , HT29 Cells , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Indoles/chemistry , Inhibitory Concentration 50 , Mice, Nude , Molecular Structure , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Polymerization/drug effects , Sulfonamides/chemistry , Sulfonamides/pharmacology , Tubulin/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Agents that interfere with mitotic progression by disturbing microtubule dynamics are commonly used for cancer treatment. Previously, a series of aroylquinolone regioisomers as novel microtubule inhibitors were discovered. One of these new compounds, MPT0B214 inhibited tubulin polymerization through strongly binding to the tubulin's colchicine-binding site and had cytotoxic activity in a variety of human tumor cell lines. After treatment with MPT0B214, KB cells were arrested in the G2-M phase before cell death occurred, which were associated with upregulation of cyclin B1, dephosphorylation of Cdc2, phosphorylation of Cdc25C and elevated expression of the mitotic marker MPM-2. Furthermore, the compound induced apoptotic cell death through mitochondria/caspase 9-dependent pathway. Notably, several KB-derived multidrug-resistant cancer cell lines were also sensitive to MPT0B214 treatment. These findings showed that MPT0B214 is a potential compound in the treatment of various malignancies.
Subject(s)
Aminoquinolines/pharmacology , Antineoplastic Agents/pharmacology , Microtubules/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Signal Transduction/drug effects , Tubulin Modulators/pharmacology , ATP Binding Cassette Transporter, Subfamily B/genetics , Aminoquinolines/chemistry , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Apoptosis/genetics , Binding Sites , Cell Cycle Checkpoints/drug effects , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/metabolism , Cytochromes c/metabolism , Drug Resistance, Neoplasm/genetics , Gene Expression , Gene Expression Regulation, Neoplastic/drug effects , Humans , Inhibitory Concentration 50 , Membrane Potential, Mitochondrial/drug effects , Phosphorylation/drug effects , Protein Binding , Protein Multimerization/drug effects , Protein Transport/drug effects , Proto-Oncogene Proteins c-bcl-2/metabolism , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/chemistryABSTRACT
Microtubule inhibitors have been shown to inhibit hypoxia-inducible factor-1α (HIF-1α) expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1α mRNA. We recently discovered a novel indoline-sulfonamide compound, 7-aryl-indoline-1-benzene-sulfonamide (MPT0B098), as a potent microtubule inhibitor through binding to the colchicine-binding site of tubulin. MPT0B098 is active against the growth of various human cancer cells, including chemoresistant cells with IC50 values ranging from 70 to 150 nmol/L. However, normal cells, such as human umbilical vein endothelial cells (HUVEC), exhibit less susceptibility to the inhibitory effect of MPT0B098 with IC50 of 510 nmol/L. Similar to typical microtubule inhibitors, MPT0B098 arrests cells in the G2-M phase and subsequently induces cell apoptosis. In addition, MPT0B098 effectively suppresses VEGF-induced cell migration and capillary-like tube formation of HUVECs. Distinguished from other microtubule inhibitors, MPT0B098 not only inhibited the expression levels of HIF-1α protein but also destabilized HIF-1α mRNA. The mechanism of causing unstable of HIF-1α mRNA by MPT0B098 is through decreasing RNA-binding protein, HuR, translocation from the nucleus to the cytoplasm. Notably, MPT0B098 effectively suppresses tumor growth and microvessel density of tumor specimens in vivo. Taken together, our results provide a novel mechanism of inhibiting HIF-1α of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies.
Subject(s)
Adenocarcinoma/drug therapy , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Lung Neoplasms/drug therapy , RNA, Messenger/metabolism , Sulfonamides/pharmacology , Tubulin Modulators/pharmacology , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma of Lung , Animals , Apoptosis/drug effects , Cell Line, Tumor , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Indoles/pharmacology , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Mice , Mice, Nude , Microtubules/genetics , Microtubules/metabolism , RNA, Messenger/genetics , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
A variety of functionalities were introduced at 2-aroylquinoline's C5 position, which is considered equivalent to C-3' of the B-ring of CA4, via Suzuki arylation, Sonogashira ethynylation, and Rosenmund-von Braun cyanation. These substitutions are rarely utilized in the modification of 3'-OH of CA4. The resulting products 6 and 7 having cyano and ethynyl groups exhibited comparable antiproliferative and tubulin inhibitory activities to colchicine.
Subject(s)
Acetylene/chemistry , Antineoplastic Agents/chemical synthesis , Chemistry Techniques, Synthetic/methods , Cyanates/chemistry , Quinolines/chemical synthesis , Tubulin Modulators/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/pharmacology , Drug Resistance, Neoplasm , Humans , Molecular Structure , Quinolines/chemistry , Quinolines/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
A variety of studies on the modification of combretastatin A-4 triggered our interest in the impact of the linkers between the 3,4,5-trimethoxyphenyl ring and 5-amino-6-methoxyquinoline on biological activity. The replacement of the carbonyl group with bond, amine, ether, sulfide, and sulfone groups was evaluated in this study. The results showed that compounds 14 and 15 containing sulfide and sulfone groups between the 3,4,5-trimethoxyphenyl ring (A-ring) and 5-amino-6-methoxyquinoline exhibited substantial antiproliferative activity against KB, HT29, and MKN45 cells with mean IC50 values of 42 and 12 nM, respectively. 15 inhibited the tubulin polymerization with an IC50 value of 2.0 µM, similar to that with CA4. The continued work on the C-5 substituents of 3',4',5'-trimethoxybenzoyl-6-methoxyquinoline derivatives demonstrated that compound 7 possessing OH at C-5 exhibited excellent antiproliferative activity with mean IC50 values of 3.4 nM and microtubule destabilizing potency with an IC50 of 1.5 µM, comparable to that of CA4 (IC50=1.9 µM). It also exhibited substantial vascular disrupting effects. Compounds 7 and 15 exhibited significant efficacy against MDR/MRP-related drug-resistant cell lines (KB-vin10, KB-S15, and KB-7D) with mean IC50 values of 6.7 and 2.6 nM, respectively.
Subject(s)
Aminoquinolines/chemical synthesis , Antineoplastic Agents/chemical synthesis , Hydroxyquinolines/chemical synthesis , Quinolines/chemical synthesis , Sulfones/chemical synthesis , Tubulin Modulators/chemical synthesis , Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/pharmacology , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Human Umbilical Vein Endothelial Cells , Humans , Hydroxyquinolines/chemistry , Hydroxyquinolines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Stilbenes/pharmacology , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
A novel series of the biheterocycles-based compounds with core structure distinguished from combretastatin A-4 (1) and colchicine (5) have been synthesized and evaluated as potent anti-mitotic agents. Compound 1-(4'-Indolyl and 6'-quinolinyl)-4,5,6-trimethoxyindoles 13 and 19 showed substantial anti-proliferative activity against various human cancer cell lines, regardless to the tissue origin and the expression of multiple-drug resistance MDR1, with a mean IC(50) value of 38 and 24 nM respectively. Compound 13 (IC(50) = 1.7 µM) also exhibited similar anti-tubulin activities to 1 (IC(50) = 1.8 µM) and displayed strong binding property to the colchicine binding site on the microtubules. Computational modeling analysis revealed that the binding mechanism of compound 13 is similar to that of CA4.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Indoles/chemistry , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Models, Molecular , Spectrometry, Mass, Electrospray Ionization , Tubulin/metabolismABSTRACT
In an attempt to mimic the 3,4,5-trimethoxyphenyl-Z-stilbene moiety of combretastatin A-4, a series of N-aryl-5,6,7-trimethoxyindoles were synthesized via copper-catalyzed Ullmann-type N-arylation through the corresponding 5,6,7-trimethoxyindole and aryl halides. These synthesized compounds demonstrated potent antiproliferative activity providing a novel skeleton for potent tubulin polymerization inhibitors.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Antimitotic Agents/chemical synthesis , Copper/chemistry , Indoles/chemical synthesis , Angiogenesis Inhibitors/pharmacology , Antimitotic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Indoles/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
Utilizing scaffold-hopping drug-design strategy, we sought to identify a backup drug candidate for BPR0L075 (1), an indole-based anticancer agent. For this purpose, 5,6-fused bicyclic heteroaromatic scaffolds were designed and synthesized through shuffling of the nitrogen from the N-1 position or by insertion of one or two nitrogen atoms into the indole core of 1. Among these, 7-azaindole core 12 showed potent in vitro anticancer activity and improved oral bioavailability (F = 35%) compared with 1 (F < 10%).
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacology , Administration, Oral , Antineoplastic Agents/administration & dosage , Biological Availability , Bridged Bicyclo Compounds/administration & dosage , Cell Line, Tumor , HumansABSTRACT
A series of 2-aroyl and 2-aryl-5,6,7-trimethoxyquinoline and 4-aroyl-6,7,8-trimethoxyquinoline combretastatin analogs were synthesized and evaluated for their potential anticancer activity. The 4-aroylquinoline 11 inhibited the growth of the human cancer cells lines KB, HT-29, and MKN45, as well as the three human resistant cancer cell lines KB-vin10, KB-S15, and KB-7D, with IC50 values of 217, 327, 239, 246, 213, and 252 nM, respectively.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Cell Line, Tumor , HumansABSTRACT
BPR0C261 is a synthetic small molecule compound cytotoxic against human cancer cells and active prolonging the lifespan of leukemia mice. In the present study, we further investigated the mechanisms of its anticancer action and found that BPR0C261 inhibited microtubule polymerization through interacting with the colchicine binding sites on tubulins, disrupted microtubule arrangement and caused cell cycle arrest at G(2)/M phase in cancer cells. BPR0C261 also inhibited the clonogenic growths of cancer cells and showed cytotoxicity against human cervical cancer cells of multidrug-resistant phenotype. In addition, BPR0C261 concentration-dependently inhibited the proliferation and migration of HUVECs and disrupted the endothelial capillary-like tube formations in HUVEC and rat aorta ring cultures. Given orally, BPR0C261 inhibited angiogenesis in s.c. implanted Matrigel plugs in mice. Notably, its IC(50) values against the endothelial cell growths were approximately 10-fold lower than those against the cancer cells. It was found orally absorbable in mice and showed a good oral bioavailability (43%) in dogs. BPR0C261 permeated through the human intestinal Caco-2 cell monolayer, suggesting oral availability in humans. Orally absorbed BPR0C261 distributed readily into the s.c. xenografted tumors in nude mice in which the tumor tissue levels of BPR0C261 were found oral dose-dependent. BPR0C261 showed in vivo activities against human colorectal, gastric, and nasopharyngeal tumors in nude mice. Most interestingly, the combination of BPR0C261 plus cisplatin synergistically prolonged the lifespans of mice inoculated with murine leukemia cells. Thus, BPR0C261 is a novel orally active tubulin-binding antitumor agent with antimitotic, apoptosis-inducing, and vasculature disrupting activities.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Antimitotic Agents/pharmacology , Antineoplastic Agents/pharmacology , Indoles/pharmacology , Thiazoles/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Dogs , Humans , Leukemia, Experimental/drug therapy , Male , Mice , Mice, Inbred Strains , Microtubules/chemistry , Microtubules/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Anti-mitotic compounds (microtubule de-stabilizers) such as vincristine and vinblastine have been shown clinically successful in treating various cancers. However, development of drug-resistance cells limits their efficacies in clinical situations. Therefore, experiments were performed to determine possible drug resistance mechanisms related to the application of anti-mitotic cancer therapy. PRINCIPAL FINDINGS: A KB-derived microtubule de-stabilizer-resistant KB-L30 cancer cell line was generated for this study. KB-L30 cells showed cross-resistance to various microtubule de-stabilizers including BPR0L075, vincristine and colchicine through multiple-drug resistant (MDR)-independent mechanisms. Surprisingly, KB-L30 cells showed hyper-sensitivity to the microtubule-stabilizer, paclitaxel. Results of the RT-PCR analysis revealed that expression of both class II and III ß-tubulin was down-regulated in KB-L30 cells as compared to its parental KB cancer cells. In addition, DNA sequencing analysis revealed six novel mutation sites present in exon four of the ßI-tubulin gene. Computational modeling indicated that a direct relationship exists between ßI-tubulin mutations and alteration in the microtubule assembly and dynamic instability in KB-L30 cells and this predicted model was supported by an increased microtubule assembly and reduced microtubule dynamic instability in KB-L30 cells, as shown by Western blot analysis. CONCLUSIONS AND SIGNIFICANCE: Our study demonstrated that these novel mutations in exon four of the ßI-tubulin induced resistance to microtubule de-stabilizers and hyper-sensitivity to microtubule stabilizer through an alteration in the microtubule assembly and dynamics in cancer cells. Importantly, the current study reveals that cancer cells may acquire drug resistance ability to anti-mitotic compounds through multiple changes in the microtubule networks. This study further provided molecular information in drug selection for patients with specific tubulin mutations.