ABSTRACT
The marine alkaloid lamellarin D (LAM-D) has been recently characterized as a potent poison of human topoisomerase I endowed with remarkable cytotoxic activities against tumor cells. We report here the first structure-activity relationship study in the LAM-D series. Two groups of triester compounds incorporating various substituents on the three phenolic OH at positions 8, 14 and 20 of 6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one pentacyclic planar chromophore typical of the parent alkaloid were tested as topoisomerase I inhibitors. The non-amino compounds in group A showed no activity against topoisomerase I and were essentially non cytotoxic. In sharp contrast, compounds in group B incorporating amino acid residues strongly promoted DNA cleavage by human topoisomerase I. LAM-D derivatives tri-substituted with leucine, valine, proline, phenylalanine or alanine residues, or a related amino side chain, stabilize topoisomerase I-DNA complexes. The DNA cleavage sites detected at T downward arrow G or C downward arrow G dinucleotides with these molecules were identical to that of LAM-D but slightly different from those seen with camptothecin which stimulates topoisomerase I-mediated cleavage at T downward arrow G only. In the DNA relaxation and cleavage assays, the corresponding Boc-protected compounds and the analogues of the non-planar LAM-501 derivative lacking the 5-6 double bond in the quinoline B-ring showed no effect on topoisomerase I and were considerably less cytotoxic than the corresponding cationic compounds in the LAM-D series. The presence of positive charges on the molecules enhances DNA interaction but melting temperature studies indicate that DNA binding is not correlated with topoisomerase I inhibition or cytotoxicity. Cell growth inhibition by the 41 lamellarin derivatives was evaluated with a panel of tumor cells lines. With prostate (DU-145 and LN-CaP), ovarian (IGROV and IGROV-ET resistant to ecteinascidin-743) and colon (LoVo and LoVo-Dox cells resistant to doxorubicin) cancer cells (but not with HT29 colon carcinoma cells), the most cytotoxic compounds correspond to the most potent topoisomerase I poisons. The observed correlation between cytotoxicity and topoisomerase I inhibition strongly suggests that topoisomerase I-mediated DNA cleavage assays can be used as a guide to the development of superior analogues in this series. LAM-D is the lead compound of a new promising family of antitumor agents targeting topoisomerase I and the amino acid derivatives appear to be excellent candidates for a preclinical development.
Subject(s)
Alkaloids/chemistry , Amino Acids/chemistry , Antineoplastic Agents/chemistry , Coumarins/chemistry , DNA Topoisomerases, Type I/chemistry , DNA/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Isoquinolines/chemistry , Alkaloids/chemical synthesis , Alkaloids/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Coumarins/chemical synthesis , Coumarins/pharmacology , DNA/metabolism , DNA Topoisomerases, Type I/metabolism , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Esters/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Molecular Structure , Structure-Activity Relationship , Topoisomerase I InhibitorsABSTRACT
A new compound, IB-00208, has been isolated from the fermentation broth of an actinomycete isolated from a marine environment. The strain was identified as Actinomadura sp. by its chemical and phylogenetic characteristics. The compound shows cytotoxic activity on tumor cell lines and bactericidal activity against gram-positive bacteria.
Subject(s)
Actinomycetales/chemistry , Anti-Bacterial Agents/isolation & purification , Antineoplastic Agents/isolation & purification , Glucosides/isolation & purification , Xanthenes/isolation & purification , Actinomycetales/classification , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/classification , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/classification , Antineoplastic Agents/pharmacology , Base Sequence , DNA, Bacterial/chemistry , DNA, Ribosomal/chemistry , Fermentation , Glucosides/chemistry , Glucosides/classification , Glucosides/pharmacology , Microscopy, Electron, Scanning , Molecular Sequence Data , Molecular Structure , Phylogeny , Xanthenes/chemistry , Xanthenes/classification , Xanthenes/pharmacologyABSTRACT
Several podophyllotoxin derivatives lacking the methylenedioxy group or with different functionalization of the A-ring of the cyclolignan skeleton have been prepared and evaluated for their cytotoxic activities on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28). Most of them maintained their cytotoxicity at the microM level.
Subject(s)
Antineoplastic Agents/chemical synthesis , Lignans/chemical synthesis , Podophyllotoxin/analogs & derivatives , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor/drug effects , Dioxanes/chemical synthesis , Dioxanes/pharmacology , Dioxoles/chemical synthesis , Dioxoles/chemistry , Dioxoles/pharmacology , Drug Screening Assays, Antitumor , Humans , Lignans/pharmacology , Magnetic Resonance Spectroscopy , Mice , Models, Chemical , Molecular Structure , Podophyllotoxin/pharmacology , Structure-Activity RelationshipABSTRACT
An anhydrophytosphingosine named pachastrissamine (3) has been isolated as a cytotoxic principle of a sponge, Pachastrissa sp., and the structure including the absolute configuration determined by spectroscopic and chemical analysis.
Subject(s)
Antineoplastic Agents/isolation & purification , Porifera/chemistry , Sphingosine/isolation & purification , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Spectrum Analysis/methods , Sphingosine/analogs & derivatives , Sphingosine/chemistry , Sphingosine/pharmacology , Tumor Cells, CulturedABSTRACT
Several analogues of thuriferic acid and derivatives, with the 3,4-methylenedioxyphenyl ring replaced by naphthalene, furan, thiophene and carbazole ring systems, have been prepared. The synthetic strategy is based on a conjugate addition-alkylation methodology followed by cationic cyclization in order to obtain the isopodophyllone analogues, which are transformed in the thuriferic acids. Their cytotoxic activities against several tumour cells lines are also described.