ABSTRACT
A series of lavendamycin analogues with two, three or four substituents at the C-6, C-7 N, C-2', C-3' and C-11' positions were synthesized via short and efficient methods and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The compounds were prepared through Pictet-Spengler condensation of the desired 2-formylquinoline-5,8-diones with the required tryptophans followed by further needed transformations. Metabolism and toxicity studies demonstrated that the best substrates for NQO1 were also the most selectively toxic to NQO1-rich tumor cells compared to NQO1-deficient tumor cells.
Subject(s)
Antineoplastic Agents/chemical synthesis , Streptonigrin/analogs & derivatives , Antineoplastic Agents/metabolism , Antineoplastic Agents/toxicity , Cell Line, Tumor , Humans , NAD(P)H Dehydrogenase (Quinone)/chemistry , NAD(P)H Dehydrogenase (Quinone)/genetics , NAD(P)H Dehydrogenase (Quinone)/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Streptonigrin/chemistry , Streptonigrin/metabolism , Streptonigrin/toxicity , Structure-Activity RelationshipABSTRACT
A 1H69 crystal structure-based in silico model of the NAD(P)H:quinone oxidoreductase 1 (NQO1) active site has been developed to facilitate NQO1-directed lavendamycin antitumor agent development. Lavendamycin analogues were designed as NQO1 substrates utilizing structure-based design criteria. Computational docking studies were performed using the model to predict NQO1 substrate specificity. Designed N-acyllavendamycin esters and amides were synthesized by Pictet-Spengler condensation. Metabolism and cytotoxicity studies were performed on the analogues with recombinant human NQO1 and human colon adenocarcinoma cells (NQO1-deficient BE and NQO1-rich BE-NQ). Docking and biological data were found to be correlated where analogues 12, 13, 14, 15, and 16 were categorized as good, poor, poor, poor, and good NQO1 substrates, respectively. Our results demonstrated that the ligand design criteria were valid, resulting in the discovery of two good NQO1 substrates. The observed consistency between the docking and biological data suggests that the model possesses practical predictive power.
Subject(s)
Antineoplastic Agents/chemical synthesis , Models, Molecular , NAD(P)H Dehydrogenase (Quinone)/chemistry , Streptonigrin/analogs & derivatives , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Cell Line, Tumor , Cytochromes c/chemistry , Drug Screening Assays, Antitumor , Humans , Protein Binding , Streptonigrin/chemical synthesis , Streptonigrin/chemistry , Streptonigrin/pharmacology , Structure-Activity RelationshipABSTRACT
A series of 7-N-acyllavendamycins with zero, one or two substituents at the C-2', C-3', and C-11' were synthesized through short and efficient methods. Pictet-Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptamine or tryptophans produced the desired lavendamycins. Screening data on a panel of three ras oncogene-transformed cell lines and the non-transformed parent cell line showed that a significant number of these analogues are potent antitumor agents and appear to be particularly active against K-ras transformed cells. Compared with the corresponding quinolinediones, these novel lavendamycins are much more inhibitory toward the transformed cells indicating that the beta-carboline moiety of the lavendamycin analogues plays an important role in its potency and selective toxicity.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Quinolines/chemical synthesis , Quinolines/pharmacology , Streptonigrin/analogs & derivatives , Animals , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Mice , Mice, Inbred C57BL , Mice, Nude , Molecular Structure , Quinolines/chemistry , Rats , Stereoisomerism , Streptonigrin/administration & dosage , Streptonigrin/chemical synthesis , Streptonigrin/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Novel lavendamycin analogues with various substituents were synthesized and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. Pictet-Spengler condensation of quinoline- or quninoline-5,8-dione aldehydes with tryptamine or tryptophans yielded the lavendamycins. Metabolism studies with recombinant human NQO1 revealed that addition of NH2 and CH2OH groups at the quinolinedione-7-position and indolopyridine-2'-position had the greatest positive impact on substrate specificity. The best and poorest substrates were 37 (2'-CH2OH-7-NH2 derivative) and 31 (2'-CONH2-7-NHCOC3H7-n derivative) with reduction rates of 263 +/- 30 and 0.1 +/- 0.1 micromol/min/mg NQO1, respectively. Cytotoxicity toward human colon adenocarcinoma cells was determined for the lavendamycins. The best substrates for NQO1 were also the most selectively toxic to the NQO1-rich BE-NQ cells compared to NQO1-deficient BE-WT cells with 37 as the most selective. Molecular docking supported a model in which the best substrates were capable of efficient hydrogen-bonding interactions with key residues of the active site along with hydride ion reception.
Subject(s)
Antineoplastic Agents/chemical synthesis , Models, Molecular , NAD(P)H Dehydrogenase (Quinone)/chemistry , NAD(P)H Dehydrogenase (Quinone)/metabolism , Streptonigrin/analogs & derivatives , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Binding Sites , Cell Line, Tumor , Drug Screening Assays, Antitumor , Electrochemistry , Humans , Hydrogen Bonding , Oxidation-Reduction , Streptonigrin/chemical synthesis , Streptonigrin/metabolism , Streptonigrin/pharmacology , Structure-Activity RelationshipABSTRACT
[structure: see text] Novel 6-substituted lavendamycins have been synthesized for the first time. The key step in these syntheses is a Pictet-Spengler condensation (Scheme 1). Efficient methods for the synthesis of each compound, including a novel reaction for the facile introduction of alkylamino groups at the C-6 position of the lavendamycin system, are discussed. Possible mechanisms for these reactions are also presented.
Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Streptomyces/chemistry , Streptonigrin/analogs & derivatives , Streptonigrin/chemical synthesis , Catalysis , Indicators and Reagents , Molecular Structure , Structure-Activity RelationshipABSTRACT
FT Raman and FTIR spectra of Naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) and its deuterated analogue are recorded. Comparison between the spectra obtained by two techniques, a series of density functional theory (DFT) calculations and the spectral behavior upon deuteration were used for the assignment of the vibrational spectra of this compound. The calculated vibrational frequencies by the B3LYP, B3PW91, G96LYP, G96P86, and MPWLYP density functionals are generally consistent with the observed spectra. Infrared and Raman vibrational transitions predicted by B3LYP/6-311++G** are reported for the titled compound and its deuterated analogous and the assignments are discussed. All experimental and theoretical results support a relatively weak hydrogen bond in naphthazarin (NZ), compared with that in the enol form of normal beta-diketones. The observed nuOH/nuOD and gammaOH/gammaOD appear at about 3060/2220 and 790/560 cm(-1), respectively, which are consistent with the calculated hydrogen bond geometry and proton chemical shift results. Two bands at about 350 and 290 cm(-1) are assigned to the O...O stretching modes belong to A1 and B2 species, respectively.
Subject(s)
Naphthoquinones/chemistry , Spectroscopy, Fourier Transform Infrared/methods , Spectrum Analysis, Raman/methods , Hydrogen Bonding , Ketones/chemistry , Magnetic Resonance Spectroscopy , Models, Chemical , Models, Theoretical , Normal Distribution , Protons , Spectrophotometry/methods , Spectrophotometry, InfraredABSTRACT
Novel lavendamycins including two water soluble derivatives were synthesized via short and efficient methods. Pictet-Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptophans produced lavendamycin esters or amides 11-17. Lavendamycins 18-21 were obtained, respectively, by further transformations of 13-15 and 17. Several lavendamycins were found to be potent HIV reverse transcriptase inhibitors with very low toxicity in vitro and in vivo. Several compounds also acted either additively or synergistically to inhibit enzyme activity together with AZT-triphosphate.
Subject(s)
Amides/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , Reverse Transcriptase Inhibitors/chemical synthesis , Streptonigrin/analogs & derivatives , Streptonigrin/chemical synthesis , Zidovudine/analogs & derivatives , Amides/pharmacology , Amides/toxicity , Animals , Cells, Cultured , Dideoxynucleotides , Drug Synergism , Esters/chemical synthesis , Esters/pharmacology , Esters/toxicity , Humans , Mice , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/toxicity , Streptonigrin/pharmacology , Streptonigrin/toxicity , Structure-Activity Relationship , Thymine Nucleotides/pharmacology , Zidovudine/pharmacologyABSTRACT
Lavendamycin is a bacterially derived quinolinedione that displays significant antimicrobial and antitumor activities. However, preclinical development of lavendamycin as an anticancer agent was halted due to the poor aqueous solubility and relatively nonspecific cytotoxic activity of this compound. In this report, we have examined the cytotoxic activities of a series of novel lavendamycin analogues. The cytotoxic activities of these compounds were evaluated in clonogenic survival assays with A549 lung carcinoma cells. Compounds bearing an amide or amine substituent at the R(3) position were the most potent inhibitors of colony formation. MB-97, the most active member of this subgroup, decreased clonogenic outgrowth by 70% at a concentration of 10 n. Treatment of A549 cells with MB-97 led to an increase in p53 protein expression and phosphorylation and a concomitant increase in the expression of the p53 target gene, p21. Exposure of p53-positive cells to MB-97 triggered cell cycle arrest in G(1) and G(2) phases but induced a selective G(2)-phase arrest in p53-negative cells. MB-97 treatment also induced a higher level of apoptosis in p53-null cells relative to their p53-positive counterparts. Finally, MB-97 showed significant cytotoxic activity in the National Cancer Institute's panel of 60 cancer cell lines and antitumor activity in vivo in hollow fiber tumorigenesis assays.
Subject(s)
Antineoplastic Agents/pharmacology , Streptonigrin/analogs & derivatives , Streptonigrin/pharmacology , Apoptosis , Cell Cycle , Cell Line, Tumor , Flow Cytometry , G2 Phase , Humans , Immunoblotting , Mitosis , Models, Chemical , Phosphorylation , Proto-Oncogene Proteins p21(ras)/biosynthesis , Streptonigrin/chemistry , Time Factors , Tumor Suppressor Protein p53/biosynthesisABSTRACT
The novel 7-(N-formyl-, 7-(N-acetyl-, and 7-(N-isobutyrylamino)-2-methylquinoline-5,8-diones were synthesized in excellent overall yields in three steps via the nitration of the commercially available 8-hydroxy-2-methylquinoline followed by a reduction-acylation step and then oxidation. Acid hydrolysis of 7-(N-acetylamino)-2-methylquinoline-5,8-dione (14a) afforded the novel 7-aminoquinoline-5,8-dione 7 in excellent yields. Due to our efficient preparation of dione 14a, we now report a short and practical method for the total synthesis of the potent antitumor agent lavendamycin methyl ester (1b) with an excellent overall yield.