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1.
J Asian Nat Prod Res ; 26(9): 1057-1086, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38920368

ABSTRACT

Modifications at different positions on the aloperine molecule were performed to improve its anticancer activity and develop anticancer drugs. The in vitro anticancer activities of 44 synthesized compounds were evaluated. The effect of modification positions on anticancer activity was discussed and a structure-activity relationship analysis was established. A novel series of compounds with modifications at the N12 position showed much higher cytotoxicity than aloperine. Among them, compound 22 displayed promising in vitro anticancer activity against PC9 cells with a median inhibitory concentration (IC50) of 1.43 µM. The mechanism studies indicated that compound 22 induced cell apoptosis and cell cycle arrest in PC9 cells. These results demonstrate the potential of aloperine thiourea derivatives in anticancer activity.


Subject(s)
Antineoplastic Agents , Apoptosis , Drug Screening Assays, Antitumor , Piperidines , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Humans , Structure-Activity Relationship , Molecular Structure , Apoptosis/drug effects , Piperidines/pharmacology , Piperidines/chemistry , Piperidines/chemical synthesis , Drug Design , Quinolizidines/pharmacology , Quinolizidines/chemistry , Quinolizidines/chemical synthesis , Cell Line, Tumor , Cell Cycle Checkpoints/drug effects
2.
J Asian Nat Prod Res ; 26(2): 259-268, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38347748

ABSTRACT

A series of novel substituted uracil-1'(N)-acetic acid esters (5-9) and 4-pyridone-1'(N)-acetic acid esters (10-11) of 20(S)-camptothecins (CPTs) have been synthesized by the acylation method. All of these new esters were assayed for in vitro cytotoxicity against five human cancer cell lines A549, Bel7402, BGC-823, HCT-8 and A2780. The in vitro bioassay results showed that all the synthesized compounds 5-11 had cytotoxities that were higher than TPT and comparable to CPT on these five tumor cell lines, some of them even showed comparable or superior cytotoxic activity to CPT. The in vitro data exhibited the cytotoxicity of the ester depended on that of its parent compound. The ester 5, 6, 8, 10, 11 even possessed the cytotoxity activity comparable to or even a little better than CPT on A549, HCT-8 and A2780. The compound 11 had the same level of cytoxity on Bel7402 as that of CPT. Here the synthesis and the in vitro antitumor evaluation of a series of novel 20-O-linked substituted uracil-1'(N)-acetic acid and 4-pyridone-1'(N)-acetic acid esters derivatives of CPTs are reported.


Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Pyridones , Humans , Female , Acetic Acid , Cell Line, Tumor , Uracil/pharmacology , Drug Screening Assays, Antitumor , Camptothecin/pharmacology , Antineoplastic Agents/pharmacology , Esters/pharmacology , Structure-Activity Relationship
3.
Bioorg Chem ; 140: 106760, 2023 11.
Article in English | MEDLINE | ID: mdl-37647806

ABSTRACT

A series of new thiadiazine derivatives including 2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) propanoic acids (a) and 4-methyl-2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) pentanoic acids (b) were synthesized by reacting primary alkyl/aryl amines with CS2, followed by reaction with formaldehyde and amino acids. The chemical structures of synthesized compounds were confirmed by 13C- NMR and 1H- NMR techniques. The inhibitory potential of major inflammatory enzymes, COX-2 and 5-LOX was examined. Moreover, anti-nociceptive and anti-inflammatory activities were evaluated in the in vivo thermally induced nociceptive, and carrageenan induced paw edema models in mice. The in-vitro results reflect that these compounds exhibited concentration dependent inhibition of COX-2 and 5-LOX. The tested compounds at 50 mg/kg showed significant effect on thermally induced pain, and reduced latency time (seconds) as compared to the vehicle treated animals. Moreover, tested compounds exhibited percent inhibition of paw edema in the carrageenan induced paw edema model in mice. Furthermore, the binding modes of the most active COX-2 and 5-LOX inhibitors were determined through computational methods. The computational study reflects that the docked compounds have high binding affinities for COX-2 and 5-LOX enzymes, which leads to inhibition of these enzymes.


Subject(s)
Thiadiazines , Animals , Mice , Carrageenan , Cyclooxygenase 2 , Amines , Amino Acids
4.
J Asian Nat Prod Res ; 22(12): 1188-1196, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33176482

ABSTRACT

There are no effective antiviral drugs to treat hand, foot, and mouth disease. In this study, a series of lycorine derivatives were synthesized and evaluated against enterovirus 71 and coxsackievirus A16 in vitro. Derivatives 7c-m with the phenoxyacyl group at the C-1 position showed higher efficacy and lower toxicity than lycorine. In addition, derivative 7e enhanced the survival rate to 40% in the mouse model of the lethal EV71 infection.


Subject(s)
Antiviral Agents , Enterovirus A, Human , Enterovirus , Hand, Foot and Mouth Disease , Amaryllidaceae Alkaloids , Animals , Antiviral Agents/pharmacology , Mice , Molecular Structure , Phenanthridines
5.
RSC Adv ; 10(57): 34938-34942, 2020 Sep 16.
Article in English | MEDLINE | ID: mdl-35514391

ABSTRACT

An efficient and mild method has been developed for the amination of ß-methoxy amides (γ-lactones) including natural products michelolide, costunolide and parthenolide derivatives by using lithium chloride in good yields. This reaction is applicable to a wide range of substrates with good functional group tolerance. Mechanism studies show that the reactions undergo a LiCl promoted MeOH elimination from the substrates to form the corresponding α,ß-unsaturated intermediates followed by the Michael addition of amines.

6.
Eur J Med Chem ; 125: 1235-1246, 2017 Jan 05.
Article in English | MEDLINE | ID: mdl-27871039

ABSTRACT

A series of novel substituted uracil-1'(N)-acetic acid esters (6-20) of camptothecins (CPTs) were synthesized by the acylation method. These new compounds were evaluated for in vitro antitumor activity against tumor cell lines, A549, Bel7402, BGC-823, HCT-8 and A2780. In vitro results showed that most of the derivatives exhibited comparable or superior cytotoxicity compare to CPT (1) and topotecan (TPT, 2), with 12 and 13 possessing the best efficacy. Four compounds, 9, 12, 13 and 16, were selected to be evaluated for in vivo antitumor activity against H22, BGC-823 and Bel-7402 in mice. In vivo testing results indicated that 12 and 13 had antitumor activity against mouse liver carcinoma H22 close to Paclitaxel and cyclophosphamide. 12 had similar antitumor activity against human gastric carcinoma BGC-823 in nude mice compared to irinotecan (3) and possessed better antitumor activity against human hepatocarcinoma Bel-7402 in nude mice than 2. It is also discovered that 12 showed a similar mechanism but better inhibitory activity on topoisomerase I (Topo I) compared to 2. These findings indicate that 20(S)-O-fluorouracil-1'(N)-acetic acid ester derivative of CPTs, 12, could be developed as an antitumor drug candidate for clinical trial.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Neoplasms/drug therapy , Uracil/analogs & derivatives , Uracil/therapeutic use , Acetates/chemical synthesis , Acetates/chemistry , Acetates/pharmacology , Acetates/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Camptothecin/chemical synthesis , Camptothecin/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , DNA Topoisomerases, Type I/metabolism , Humans , Mice, Nude , Neoplasms/metabolism , Neoplasms/pathology , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/pharmacology , Topoisomerase I Inhibitors/therapeutic use , Uracil/chemical synthesis , Uracil/pharmacology
7.
J Asian Nat Prod Res ; 15(11): 1179-88, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24215541

ABSTRACT

In an attempt to improve the antitumor activity of homocamptothecins (hCPTs), a series of novel 20-O-linked hCPT ester derivatives were first designed and synthesized based on a synthetic route, by which hCPTs are acylated with different substituted phenoxyacetic acid ester derivatives. Most of the derivatives were assayed for in vitro cytotoxicity against six human cancer cell lines KB, KB/VCR, A549, HCT-8, Bel7402, and A2780, and most of the assayed compounds exhibited good antiproliferative activity on these tumor cell lines especially on KB.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Camptothecin/analogs & derivatives , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Antineoplastic Agents/chemistry , Camptothecin/chemical synthesis , Camptothecin/chemistry , Camptothecin/pharmacology , Drug Screening Assays, Antitumor , Esters , Humans , Inhibitory Concentration 50 , KB Cells , Molecular Structure , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemistry
8.
Chem Pharm Bull (Tokyo) ; 58(2): 208-11, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20118580

ABSTRACT

A series of phthiobuzone analogs, prepared from potassium phthalimide or phthalandione, have been evaluated for their antiviral activities. Among the candidates, compounds 5j and 5k, which contain the substituted 4-halogenated phenyl ring at N-4',4'' position, show more potent antiviral activity than phthiobuzone against herpes simplex virus 1 (IC(50)=8.56 and 2.85 microg/ml, respectively) and herpes simplex virus 2 (IC(50)=1.75 and 4.11 microg/ml, respectively). Compounds 9c and 9d with a propylene linker between the phthalimide and bisthiosemicarbazone moieties display similar antiviral potency against herpes simplex virus 1 (IC(50)=2.85 and 4.11 microg/ml, respectively).


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Herpes Simplex/drug therapy , Herpesvirus 1, Human/drug effects , Herpesvirus 2, Human/drug effects , Phthalimides/chemistry , Phthalimides/pharmacology , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacology , Animals , Antiviral Agents/chemical synthesis , Cell Proliferation/drug effects , Chlorocebus aethiops , Molecular Structure , Phthalimides/chemical synthesis , Structure-Activity Relationship , Thiosemicarbazones/chemical synthesis , Vero Cells
9.
Yao Xue Xue Bao ; 41(11): 1057-63, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17262947

ABSTRACT

AIM: To search for colchicine derivatives which have high efficacy and low toxicity. METHODS: Colchicine was firstly converted into thiocolchicine, and then it was hydrolyzed to get 7-(N-deacetylthiocolchicine). At last, 7-(N-deacetylthiocolchicine) was amidated to get the target compounds. The chemical structure of these new derivatives was confirmed with 1H NMR, IR, MS, and HR-MS. The cytotoxicity of the compounds was tested by MTT assay. Their in vivo antitumor activity was evaluated against mice tumor H22 and U14. RESULTS: Twelve thiocolchicine derivatives are new compounds. CONCLUSION: In vitro antitumor activity has showed that some of these thiocolchicines possessed cytotoxic activity superior to colchicine. However, in vivo antitumor activity indicated that these derivatives have poor efficacy in mice.


Subject(s)
Colchicine/analogs & derivatives , Liver Neoplasms, Experimental/prevention & control , Prostatic Neoplasms/prevention & control , Animals , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Colchicine/chemical synthesis , Colchicine/chemistry , Colchicine/pharmacology , Humans , Inhibitory Concentration 50 , Liver Neoplasms, Experimental/pathology , Male , Mice , Mice, Inbred ICR , Models, Chemical , Molecular Structure , Neoplasm Transplantation , Prostatic Neoplasms/pathology , Structure-Activity Relationship
10.
Yao Xue Xue Bao ; 40(3): 241-7, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15952596

ABSTRACT

AIM: To improve the biological activity of A-ring modified analogues of camptothecin. METHODS: A-ring modified camptothecins were synthesized from 10-hydroxycamptothecin or 7-ethyl-10-hydroxycamptothecin (SN-38) in three or four steps. Their cytotoxicity was evaluated using MTY assay, and their in vivo antitumnor activity against mouse liver cancer H22 was tested. Results Five hexacyclic camptothecins (6a, 6b, 6c, 7a and 7b) are target compounds, and ten camptothecin derivatives are new compounds. CONCLUSION: The modification of a 1,4-oxazine-2-one ring fused with positions 9 and 10 of A-ring will reduce the antitumor activity of camptothecins.


Subject(s)
Antineoplastic Agents/chemical synthesis , Camptothecin/analogs & derivatives , Camptothecin/chemical synthesis , Polycyclic Compounds/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Camptothecin/chemistry , Camptothecin/pharmacology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor/drug effects , Female , Humans , Irinotecan , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Mice , Neoplasm Transplantation , Polycyclic Compounds/pharmacology
11.
Yao Xue Xue Bao ; 39(8): 591-7, 2004 Aug.
Article in Chinese | MEDLINE | ID: mdl-15563058

ABSTRACT

AIM: To improve the profile of 20 (S)-camptothecin, a series of 20-O-linked camptothecin phenoxyacetic acid ester derivatives have been designed. METHODS: These derivatives were synthesized by the method of acylation. Their chemical structures were confirmed with 1HNMR, IR, MS, and HRMS. The cytotoxicities of the compounds were tested by MTT assay. The in vivo antitumor activities of these esters were evaluated against mouse liver tumor H22 in mice. RESULTS: Twelve derivatives of camptothecin ester are new compounds. CONCLUSION: In vitro and in vivo antitumor activity has indicated that some derivatives appeared significantly more effective than topotecan in the H22 mouse liver tumoral model.


Subject(s)
Antineoplastic Agents/chemical synthesis , Camptothecin/chemical synthesis , Camptothecin/pharmacology , Liver Neoplasms/pathology , Topotecan/analogs & derivatives , Topotecan/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Camptothecin/chemistry , Cell Line, Tumor/drug effects , Esters/chemistry , Female , Humans , Inhibitory Concentration 50 , Mice , Mice, Inbred ICR , Molecular Structure , Neoplasm Transplantation , Topotecan/chemistry , Topotecan/pharmacology , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
12.
Bioorg Med Chem ; 12(13): 3657-62, 2004 Jul 01.
Article in English | MEDLINE | ID: mdl-15186850

ABSTRACT

A series of nitrogen-based 20S-hydroxyl camptothecin ester derivatives were prepared. 3-Aminopropionate of camptothecin was found more cytotoxic in vitro on several human tumor cell lines than 3-amidopropionate of camptothecin. Ester 16 showed best antitumor activity in vivo and in vitro in all esters we prepared.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Camptothecin/chemical synthesis , Camptothecin/therapeutic use , Esters/chemistry , Nitrogen/chemistry , Animals , Antineoplastic Agents/chemistry , Camptothecin/analogs & derivatives , Camptothecin/chemistry , Cell Line, Tumor , Female , Humans , Inhibitory Concentration 50 , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Molecular Structure , Xenograft Model Antitumor Assays
13.
Bioorg Med Chem Lett ; 13(21): 3739-41, 2003 Nov 03.
Article in English | MEDLINE | ID: mdl-14552770

ABSTRACT

A series of 7-acyloxymethylcamptothecin and 20-O-acyl-7-acyloxymethylcamptothecin derivatives were regioselectively prepared on different solvents. 7-Acyloxymethylcamptothecins possess more efficacy than 20-O-acyl-7-acyloxymethylcamptothecins against six human cancer cell lines in vitro.


Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Camptothecin/chemical synthesis , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Solvents , Structure-Activity Relationship
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