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1.
J Enzyme Inhib Med Chem ; 24(5): 1169-78, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19555167

ABSTRACT

A number of 1,8-naphthyridine derivatives (22-62) have been synthesized and screened for their in vitro cytotoxicity against eight tumors and two non-tumor cell lines. Halogen substituted 1,8-naphthyridine-3-caboxamide derivatives showed potent activity with compound 47 having IC(50) of 0.41 and 0.77 microM on MIAPaCa and K-562 cancer cell lines, respectively while, compound 36 had IC(50) of 1.19 microM on PA-1 cancer cell line. However, one of the unsubstituted 1,8-naphthyridine-C-3'-heteroaryl derivative 29 showed potent cytotoxicity with IC(50) of 0.41 and 1.4 microM on PA-1 and SW620 cancer cell lines, respectively. These compounds were also evaluated for anti-inflammatory activity as suggested by downregulation of proinflammaotory cytokines.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Immunologic Factors/chemical synthesis , Immunologic Factors/pharmacology , Naphthyridines , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Molecular Structure , Naphthyridines/chemical synthesis , Naphthyridines/chemistry , Naphthyridines/pharmacology
2.
J Enzyme Inhib Med Chem ; 24(3): 763-70, 2009 Jun.
Article in English | MEDLINE | ID: mdl-18720190

ABSTRACT

A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC(50) = 5.67 microm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC(50) = 6.1 microm) and oral (IC(50) = 4.17 microm) cancers. These compounds could be of use in designing new anti-cancer agents.


Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Amino Acids/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Amides/chemistry , Antineoplastic Agents/chemistry , Cell Line , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Fibroblasts/cytology , Fibroblasts/drug effects , Humans , Inhibitory Concentration 50 , Mouth Neoplasms/pathology , Ovarian Neoplasms/pathology
3.
Bioorg Med Chem Lett ; 18(18): 5058-62, 2008 Sep 15.
Article in English | MEDLINE | ID: mdl-18752941

ABSTRACT

A new series of betulinic acid derivatives have been synthesized by introducing heterocyclic ring between C-2 and C-3 positions of betulinic acid. Further modifications were also carried out by reduction of C-20(29) unsaturated bond and substitution of C-28 carboxyl group by ester and amide linkage to enhance the selectivity. Compound 11 resulted in IC(50) of 2.44, 2.5, and 2.7 microg/ml on MIAPaCa, PA-1, and SW620 cancer cell lines, respectively. Compound 38 resulted in IC(50) of 0.67 microg/ml on MIAPaCa cell line.


Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Triterpenes/chemical synthesis , Triterpenes/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Combinatorial Chemistry Techniques , Drug Screening Assays, Antitumor , Female , Humans , Inhibitory Concentration 50 , Male , Molecular Structure , Pentacyclic Triterpenes , Structure-Activity Relationship , Triterpenes/chemistry , Betulinic Acid
4.
Invest New Drugs ; 26(6): 505-16, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18322652

ABSTRACT

We have reported earlier a novel combination of four structurally designed synthetic neuropeptide analogs of vasoactive intestinal peptide (VIP), bombesin, substance P and somatostatin, code-named DRF 7295 which have anti-tumor efficacy for adenocarcinomas in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). The discovery, synthesis, in vitro and in vivo efficacy was reported (Jaggi et al., Invest New Drugs, 2008). Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to most sensitive to DRF7295 in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). We have further investigated and report here the modulation of cellular signaling in gastrointestinal carcinomas by DRF 7295, which may be mediating its observed anticancer activity in these cancer types. DRF 7295 inhibits the binding of specific neuropeptides initiating a cascade of cellular signaling events leading to programmed cell death. It down regulates the second messenger cAMP, epidermal growth factor (EGF) dependent proliferation and the phosphorylated MAP Kinase pERK1/2 in gastrointestinal carcinomas, thus depriving the tumour cells of critical pro-proliferative cellular signals. It triggers bcl2 and Caspase 3 dependent apoptotic cell death and induces p53 tumor suppressor protein in the treated carcinoma cells in vitro. It has significant anti-angiogenic potential as reflected in the inhibition of tube like formation in the endothelial cells and down regulation of VEGF levels. Tumour xenograft studies confirmed the in vivo efficacy of DRF 7295 for gastrointestinal carcinomas (Jaggi et al., Invest New Drugs, 2008). The Phase I clinical trials have shown DRF 7295 to be well tolerated and devoid of systemic toxicities of the conventional cytotoxics (Mukherjee et al., Phase I dose escalating study of DRF7295: a new class of peptide based drugs. "Abstract" ASCO ID:948, 2003). The drug may have a promising role in disease stabilization in colorectal and other cancers. Thus DRF 7295 is a novel targeted drug in the class of signal transduction modulators, with potential for treatment of gastrointestinal carcinomas.


Subject(s)
Antineoplastic Agents/pharmacology , Gastrointestinal Neoplasms/drug therapy , Peptides/pharmacology , Signal Transduction/drug effects , Apoptosis/drug effects , Caspase 3/drug effects , Caspase 3/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclic AMP/metabolism , Down-Regulation/drug effects , Drug Combinations , Drug Screening Assays, Antitumor/methods , Epidermal Growth Factor/drug effects , Epidermal Growth Factor/metabolism , Gastrointestinal Neoplasms/physiopathology , Humans , Mitogen-Activated Protein Kinase 1/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/drug effects , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-bcl-2/drug effects , Proto-Oncogene Proteins c-bcl-2/metabolism , Tumor Suppressor Protein p53/drug effects , Tumor Suppressor Protein p53/metabolism
5.
J Med Chem ; 50(8): 1744-53, 2007 Apr 19.
Article in English | MEDLINE | ID: mdl-17373779

ABSTRACT

A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.


Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis , Cyclopentanes/chemical synthesis , Stilbenes/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cyclopentanes/pharmacokinetics , Cyclopentanes/pharmacology , DNA Fragmentation , Drug Screening Assays, Antitumor , Endothelial Cells/drug effects , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Solubility , Stilbenes/pharmacokinetics , Stilbenes/pharmacology , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacokinetics , Tubulin Modulators/pharmacology
6.
J Pept Sci ; 13(1): 54-62, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17031871

ABSTRACT

Six octapeptide bombesin (BN) analogs were synthesized by substituting alpha-aminoisobutyric acid (Aib), in place of Ala9 or Gly11, or both, in the [D-Phe6, desMet14]-BN (6-14) sequence: D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Leu13-NH2 (P0). Additionally, Leu13 was replaced with isoleucine in two analogs and one of the analogs was butanoylated at the N-terminus. The antiproliferative activity of the analogs was tested in vitro on human pancreatic (MiaPaCa-2) and colon cancer (SW620, HT29 and PTC) cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The analogs demonstrated anticancer activity in the above cell lines at concentrations ranging from 0.01 nM to 1 microM. One of the analogs, P6, was evaluated for in vivo tumor regression in a xenograft model of human primary colon cancer in athymic nude mice and was found to cause significant reduction in tumor volume. NMR and molecular dynamics (MD) simulation studies for this analog revealed the presence of a mixed 3(10)/alpha-helical structure. This study demonstrates that the designed BN analogs retain their anticancer activity after the incorporation of the constrained amino acid, Aib, and are potential molecules for future use in cancer therapy and drug targeting.


Subject(s)
Aminoisobutyric Acids/chemistry , Antineoplastic Agents/pharmacology , Bombesin/pharmacology , Cell Proliferation/drug effects , Amino Acid Sequence , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Bombesin/analogs & derivatives , Bombesin/chemical synthesis , Cell Line, Tumor , Dose-Response Relationship, Drug , HT29 Cells , Humans , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred BALB C , Mice, Nude , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thermodynamics , Xenograft Model Antitumor Assays/methods
7.
Bioorg Med Chem Lett ; 16(16): 4195-9, 2006 Aug 15.
Article in English | MEDLINE | ID: mdl-16766184

ABSTRACT

A number of costunolide derivatives (4a-p) have been synthesized and evaluated for their in vitro cytotoxicity against eight tumor and a non-tumor cell lines. Compound 4d showed around 2-fold better cytotoxicity against SW-620 (colon) cell line with improved safety index than costunolide (1). While compounds 4e, 4g, and 4p have shown around 2- to 3-fold better cytotoxicity against MIAPaCa2 (pancreas), K-562 (leukemia) and PA-1 (ovary) cell lines as well as better safety index in comparison to costunolide (1). Compound 4p also exhibited cytotoxicity against HBL100 (breast) cell line with 2-fold better safety index. Structure-activity relationship has been described.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Sesquiterpenes/chemical synthesis , Animals , Cell Line , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Drug Design , Drug Screening Assays, Antitumor , Humans , K562 Cells , Mice , Models, Chemical , Sesquiterpenes/chemistry
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