Streptonigrin and related compounds. 6. Synthesis and activity of some quinoxaline analogues

Streptonigrin is an antitumor antibiotic with significant in vitro and in vivo antitumor activity spectrum. Besides the total syntheses, numerous syntheses of the partial structures have been carried out in order to assess the structural requirements for the activity. The present publication deals with the synthesis of selected quinoxalinequinones to study the effect of changes in the B-ring of streptonigrin. A convenient 3-step synthesis of the required quinoxaline starting material that provides the necessary control of the desired substituent pattern is described. A series of 7-amino-6-methoxy-quinoxalinequinones were prepared in which substitution at 3- was varied (from H to Cl, OCH₃, CN, COOCH₃ and OH). A few selected 6-aminoquinones (with 6-NH₂ and 6-piperidinyl) were also prepared for comparison. The quinones (18) were tested in three different in vitro test systems: cytotoxicity to mouse leukemia (L-1210) cells, antibacterial activity against Bacillus subtilis and inhibition of root growth. Several of the aminoquinones showed significant activity in comparison to that shown by streptonigrin.     

Acridine derivatives. IV. Synthesis,molecular structure,and antitumor activity of the novel 9-anilino-2,3-methylenedioxyacridines

In the biological and physical investigation of a new class of deoxyribonucleic acid (DNA)-intercalating antitumor agents, novel 9-anilino-2,3-methylenedioxyacridines (twelve compounds) have been synthesized and evaluated for the activity against L1210 leukemia in vivo. A few of them possessed the same potency of the antitumor activity as 4′-(9-acridinylamino)methanesulfonyl-m-anisidine (amsacrine, m-AMSA), which is an important antitumor agent in clinical use. The molecular structure of a typical one, 9a in this series have been determined by the X-ray diffraction method using a single crystal. The results of this X-ray investigation have shown that the new class of acridine derivatives have the methylenedioxy group fused at the 2- and 3-positions of the acridine ring.     

Derivatives of 5-nitro-1H-benzo[de]isoquinoline-1,3(2H)-dione: design, synthesis, and biological activity

Abstract  

A series of mono and bis-2-(2-(dimethylamino)-ethyl)-5-nitro-1H-benzo[de]isoquinoline-1,3(2H)-diones with different amino side chains, a novel family of antitumor agents, has been designed and synthesized. Their antitumor activity was evaluated against HeLa, A549, P388, HL-60, MCF-7, HCT-8, and A375 cancer cell lines in vitro. Preliminary results showed that most of the derivatives had antitumor activity comparable with that of mitonafide, with IC ₅₀ values of 10⁻⁶–10⁻⁵ M. More importantly, the derivatives had distinct antitumor selectivity against different cancer cell lines. This work provided a novel class of mitonafide-based lead compounds with improved antitumor selectivity against cancer cell lines for further optimization.     

Antimicrobial activity of 3-(substituted methyl)-2-phenyl-4H-l-benzothiopyran-4-ones

A series of 3-(substituted Methyl)-2-phenyl-4H-l-benzothiopyran-4-ones (thioflavones) and thioflavone 1,1-dioxides was prepared to test for antimicrobial activity and for antitumor activity. It was shown that an introduction of a substituted methyl group in the 3-position of thioflavone resulted in significant antimicrobial activity against Trichophytons. 3-(Acetoxymethyl)thioflavone shows the most antimicrobial potency in vitro against Trichophyton mentagrophytes. Most of the thioflavone 1,1-dioxides showed antimicrobial activity against fungi. Five of the 40 related compounds demonstrated weak antitumor activity against P-388 lymphocytic leukemia.     

Synthesis and structures of some diorganotin bis(hydroxamate)s

Analysis of literature data on the antitumor activity of organotin compounds reveals that R₂SnX₂ and their complexes containing Sn? O, Sn? N or Sn? S bonds often exhibit biological activity, especially if such bonds are formed by means of intramolecular coordination. Furthermore, a wide range of biological activities, from fungicidal, bactericidal and antiseptic to psychotropic and antitumor, is found to be characteristic for some organic hydroxamic acids (N-acylhydroxylamines). From this point of view the diorgantion bis-hydroxamates in this paper are of particular interest as potential biologically active antitumor drugs. Di-n-butyltin bis(N-methyl-N-p-bromobenzoylhydroxylamine) is being screened for antitumor activity.     

A two-plasmid system for the glycosylation of polyketide antibiotics: bioconversion of -rhodomycinone to rhodomycin D

Background: The biological activity of many microbial products requires the presence of one or more deoxysugar molecules attached to agylcone. This is especially prevalent among polyketides and is an important reason that the antitumor anthracycline antibiotics are avid DNA-binding drugs. The ability to make different deoxyaminosugars and attach them to the same or different aglycones in vivo would facilitate the synthesis of new anthracyclines and the quest for antitumor drugs. This is feasible using the numerous bacterial genes for deoxysugar biosynthesis that are now available. Results: Production of thymidine diphospho (TDP)- -daunosamine (dnm), the aminodeoxysugar present in the anthracycline antitumor drugs daunorubicin (DNR) and doxorubicin (DXR), and its attachment to -rhodomycinone to generate rhodomycin D has been achieved by bioconversion with a strain of Streptomyces lividans that bears two plasmids. One contained the Streptomyces peucetius dnmJVUZTQS genes plus dnmW (previously named dpsH and considered to be a polyketide cyclase gene), dnrH, which is not required for the formation of rhodomycin D, and dnrl, a regulatory gene required for expression of the dnm and drr genes. The other plasmid had genes encoding glucose-1-phosphate thymidylyltransferase and TDP-glucose-4,6-dehydratase (dnmL and dnmM, respectively, or mtmDE, their homologs from Streptomyces agrillaceus) plus the drrAB DNR/DXR resistance genes. Conclusions: The high-yielding glycosylation of the aromatic polyketide -rhodomycinone using plasmid-borne deoxysugar biosynthesis genes proves that the minimal information for -daunosamine biosynthesis and attachment in the heterologous host is encoded by the dnmLMJVUTS genes. This is a general approach to making both known and new glycosides of anthracyclines, several of which have medically important antitumor activity.     

Preparation,antitumor activity in mice,pharmacokinetics and tissue distribution in rats of di‐n‐butyl‐di‐(4‐chlorobenzohydroxamato)tin(IV) liposome

Di‐n‐butyl‐di‐(4‐chlorobenzohydroxamato)tin(IV) (DBDCT) is an antitumor compound with high activity and relatively low bioavailability. In order to improve the pharmacokinetic characteristics and raise its therapeutic index, a liposome of DBDCT (DBDCT‐L) was prepared for the first time. A study of the pharmacokinetics and tissue distribution after intravenous administration of DBDCT‐L compared with free DBDCT to rats was investigated. DBDCT‐L showed a slower clearance, increased half‐time and a larger AUC value than those of free DBDCT, which demonstrated that DBDCT‐L could significantly alter the tissue distribution pattern of DBDCT in rats. The highest concentration distribution for DBDCT‐L was detected in liver, which may be associated with the enhanced antitumor activity in vivo against hepatocellular carcinoma H₂₂ and possible target release of the compound. Acute toxicity assay showed that the LD₅₀ value of DBDCT‐L was higher than that of free DBDCT. Further in vivo antitumor test showed that DBDCT‐L displayed higher antitumor activity against the hepatocellular carcinoma H₂₂ than free DBDCT, indicating that the liposome could prolong the action time of DBDCT in the system circulation, change its distribution in rats, reduce acute toxicity and finally increase antitumor activity. Copyright © 2014 John Wiley & Sons, Ltd.     

o‐Carboxybenzoylferrocene. Bioactivity and chemical Modifications

The antitumor activity of o‐carboxybenzoylferrocene sodium salt ( 1 ) was studied in vivo . Interaction between o‐carboxybenzoylferrocene ( 2 ) and N,N′‐carbonyldiimidazole in boiling methylene dichloride leads to 3‐(N‐imidazolyl)‐3‐ferrocenylisobenzofuran‐1(3H)‐one ( 5 ). The structure of compound 5 was established by X‐ray analysis. Aminolysis of compound 5 in toluene gave rise to ferrocenoylbenzamides ( 6a – d )–derivatives of dimethylamine, piperidine, pyrrolidine and morpholine. Copyright © 2008 John Wiley & Sons, Ltd.     

Studies on the Constituents of Anona Squamosa L.

Anona squamosa L. (Fam. Anonaceae) has been used in folk medicine¹ as amebicide, tonic, astringent and has antitumor activity against Ehrlich cancer cell in mice^2,3. In order to search for the active constituents of Formosan antitumor plants, examination was made on the alkaloids of the roots of Anona squamosa L. Seven alkaloids (A-G) and an non-alkaloidal compound (H) were isolated from the basic and n-hexane fraction respectively. Identification of these bases by spectral analysis and direct comparison of their infrared spectra, tlc and mixed melting point have proved to be non-phenolic anonaine (I), michelalbine (III), oxoushinsunine (liriodenine) (IV) and phenolic L-(+)-reticuline (V), anolobine (VI). Examination of other two minor phenolic Base-D, mp. 224–226°, Base-E, mp. 231–233° (decomp) and an non-alkaloidal crystal-H, mp. 175–176° are now in progress.     

Synthesis and antitumor activity of new silver(I)-N-heterocyclic carbene complexes

Abstract

In this study, two novel benzimidazole-based N-heterocyclic carbene ligands (1a-b) and their silver(I) complexes (2a-b) were synthesized. All new compounds were characterized by FT-IR, LC-MS, ¹H NMR, and ¹³C NMR spectroscopies. The in vitro antitumor activities of NHC ligands (1a-b) and their silver(I) complexes (2a-b) against DU-145 human prostate cancer cells, MDA-MB-231 and MCF-7 human breast cancer cells and L-929 (normal cells adipose from mouse) were also determined using MTT analysis for 24?h, 48?h, and 72?h. The results showed that while NHC ligands did not have in vitro antitumor activity on MCF-7, MDA-MB-231 and DU-145 cells, Ag(I)-NHC complexes have in vitro antitumor activities. The in vitro antitumor activity of 2a was found to be lower than that of 2b. Ag(I)-NHC complexes were observed to have higher IC₅₀ values for non-cancerous cell lines than cancer cells.     

Iron(III) diacetylmonoxime‐2‐hydrazinopyridine complex: A new prospective antitumor drug

Because of the side effects and drug resistance of cisplatin, a basic clinically approved chemotherapeutic drug, a new attempt is reported to develop a novel antitumor drug based on complexation of iron metal ion with organic moiety that may be effective and safer. A newly synthesized iron(III) diacetylmonoxime‐2‐hydrazinopyridine complex was tested firstly for its cytotoxicity and superoxide dismutase (SOD)‐mimic activity in vitro then for its antitumor activity against Ehrlich ascites carcinoma (EAC) and the related biochemical alterations in vivo in comparison with cisplatin. The complex showed 80.88% SOD‐mimic activity and IC₅₀ of 2.6 μg ml⁻¹. In EAC‐bearing mice, in a dose‐dependent manner, Fe(III) complex treatment exhibited significant hematological profile improvements, tumor volume, viable cell count and hepatic lipid peroxidation level decreases, life span extension, hepatic glutathione and total antioxidant capacity levels enhancements, hepatic SOD and catalase activities augmentations, liver function tests alterations attenuations, and hepatocyte nucleic acids content normalization. Thus, the Fe(III) diacetylmonoxime‐2‐hydrazinopyridine complex is a novel, promising, less toxic antitumor agent. Its killing of tumor cells may be via a reactive oxygen species scavenging mechanism.     

Inhibitory Effects of New Mercapto Xanthine Derivatives in Human mcf7 and k562 Cancer Cell Lines

A series of new 2‐methyl‐2‐[(1,3‐Diethyl‐2,6‐dioxo‐2,3,6,7‐tetrahydro‐1H‐purin‐8‐yl)thio]‐N‐ substituted arylacetamides were synthesized. The antitumor activity of these purine based compounds were evaluated on breast cancer (MCF7) and leukemic cancer (K562) cell lines via cell viability assay utilizing the tetrazolium dye 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT). These results were substantiated using computer docking experiments (LigandFit docking engine and PMF scoring function) which predict that the antitumor activity of these new compounds may be attributable to their abilities to effectively bind and block oncogenic tyrosine kinases, particularly bcr/abl.     

New Ni(II), Pd(II) and Pt(II) complexes coordinated to azo pyrazolone ligand with a potent anti‐tumor activity: Synthesis,characterization, DFT and DNA cleavage studies

The absolute necessity to fight some class of tumor is perceived as serious health concerns, so the discovery and development of effective anticancer agents are urgently needed. (E)‐4‐((2‐hydroxyphenyl)diazenyl)‐3‐phenyl‐1H‐pyrazol‐5(4H)‐one, HL, and its Ni(II), Pd(II) and Pt(II) complexes were synthesized and the biological activity was evaluated for antitumor, antioxidant and antimicrobial activity as well as DNA cleavage. Their structures were assigned depending on the elemental analysis, conductivity, magnetic moment, spectral measurements (IR, ¹HNMR, mass and UV–Vis) and thermal analysis. 3D molecular modeling using DFT method confirmed that the geometrical structures agree well with the suggested experimental ones. The antitumor activity was evaluated against four different cell lines using MTT assay. The ligand HL showed a potent cytotoxic activity compared to 5‐fluorouracil as a reference drug. For metal complexes, the order of activity was: Pd(II) > Ni(II) > Pt(II). A remarkable antioxidant activity for the ligand HL was recorded. It was higher than that of the metal complexes. Results of antimicrobial experiments revealed that all compounds were moderate to highly active against selected bacterial strains but inactive as antifungal except Pd(II) which showed a moderate antifungal activity. Gel electrophoresis showed insignificant nucleases activity for the ligand or its metal complexes even in the presence of H₂O₂ providing protection of DNA from damage. The antitumor activity of our compounds may be not due to DNA cleavage but may be referred to a mechanism similar to that of 5‐fluorouracil which interfere with DNA replication. The present work suggests the use of this ligand in the design and development of new anticancer drugs.     

Novel naphthalimide–indomethacin hybrids as potential antitumor agents: effects of linkers on hypoxic/oxic cytotoxicity and apoptosis-inducing activity

Abstract  

A series of novel naphthalimide–indomethacin hybrids with different linkers were designed and synthesized. Their antitumor activity was evaluated against HeLa, A549, P388, HL-60, MCF-7, HCT-8, and A375 cancer cell lines in vitro. Preliminary results showed that the hybrids had moderate cytotoxic activity with 50% inhibition concentration (IC ₅₀) values of ~10⁻⁵ M, and could effectively induce apoptosis in HeLa cells. More importantly, the amide derivatives had better cytotoxic and proapoptotic activity than their ester counterparts, whereas the ester derivatives had hypoxic preferred cytotoxicity and might be used as promising candidates of prodrug in hypoxic tumor cells. This work provides a novel class of naphthalimide–indomethacin hybrids with unique antitumor activity for further optimization.     

Potential DNA bis-intercalating agents: Synthesis and antitumor activity of novel,conformationally restricted bis(9-aminoacridines)

A series of bis(9-aminoacridines) bridged by conformationally restricted tethers was synthesized and evaluated against L1210 in vitro. Several of these compounds were found to be highly active in this test system, with ID₅₀ values below 10^?7 M. CPK molecular models suggest that this antitumor activity can be correlated to the ability of these bis(9-aminoacridines) to form bis-intercalative complexes with DNA.     

Metal‐based antitumor,cytotoxic and antimicrobial activity: pharmacological evaluation of Knoevenagel condensate β‐diketone Schiff base thiosemicarbazone Cu(II) and Zn(II) complexes

Knoevenagel condensate Schiff base ligands [L = 3‐cinnamalideneacetylacetone‐thiosemicarbazone (CAT)/3‐cinnama‐ lideneacetylacetoneethylthiosemicarbazone (CAET)/3‐cinnamalideneacetylacetonephenylthiosemicarbazone (CAPT)] and their copper/zinc complexes were synthesized. They were characterized by analytical and spectral techniques. From these data it was found that the ligands adopt square‐planar geometry on metalation with Cu²⁺ and Zn²⁺. To evaluate the antitumor and cytotoxic activity of the synthesized complexes in mice and human cancer cell lines, the antitumor activity of the complexes was evaluated against an Ehrlich ascites carcinoma (EAC) tumor model. The activity was assessed using survival time and short‐term in vitro cytotoxic activity. Oral administration of complexes (100 mg/kg) increased the survival time. The cytotoxic activity of complexes was evaluated using human breast cancer (MDA‐MB‐231), colon cancer (HCT‐116) and nonsmall lung cancer (NCI‐H‐23) cell lines. Both the complexes possessed significant antitumor and cytotoxic activity on EAC and human cancer cell lines. The in vitro antimicrobial screening effect of the investigated compounds was also tested against the various organisms by well diffusion method. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis and in vitro cytotoxicity of novel dinuclear platinum(II) complexes containing a chiral tetradentate ligand

A series of novel dinuclear platinum(II) complexes with a chiral tetradentate ligand, (1R,1′R,2R,2′R)-N¹,N¹′-(1,2-phenylenebis(methylene))dicyclohexane-1,2-diamine (HL), and mono-carboxylic acid derivatives as ligands have been designed, synthesized, and characterized. In vitro cytotoxicity evaluation of synthesized complexes against human HepG-2, A549, HCT-116, and MCF-7 cancer cell lines has been conducted by MTT assays. All compounds showed antitumor activity to HepG-2 and HCT-116 cell lines. Compound L2 exhibited better cytotoxicity than that of carboplatin against HepG-2 and A549 cell lines and also showed comparable activity against HCT-116 cell line.     

Synthesis of certain exocyclic thiazole nucleosides related to tiazofurin. Formation of a unique acycloaminonucleoside

Several thiazole nucleosides structurally related to tiazofurin (1) and ARPP (2) were prepared, in order to determine whether these nucleosides had enhanced antitumor/antiviral activities. Ring closure of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)thiourea (4) with ethyl bromopyruvate (5a) gave ethyl 2-(2,3,5-tri-O-benzoyl-β-D-ribofuranosylamino)thiazole-4-carboxylate (6a) . Treatment of 6a with sodium methoxide furnished methyl 2-(β-D-ribopyranosylamino)thiazole-4-carboxylate (9) . Ammonolysis of the corresponding methyl ester of 6a gave a unique acycloaminonucleoside 2-[(1R, 2R, 3R, 4R)(1-benzamido-2,3,4,5-tetrahydroxypentane)amino]-thiazole-4-carboxamide (7a) . Direct glycosylation of the sodium salt of ethyl 2-mercaptothiazole-4-carboxylate (12) with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide (11) gave the protected nucleoside 10 , which on ammonolysis provided 2-(β-D-ribofuranosylthio)thiazole-4-carboxamide (3b) . Similar glycosylation of 12 with 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride (13) , followed by ammonolysis gave 2-(2-deoxy-β-D-ribofuranosylthio)thiazole-4-carboxamide (3c) . The structural assignments of 3b, 7a , and 9 were made by single-crystal X-ray analysis and their hydrogen bonding characteristics have been studied. These compounds are devoid of any significant antiviral/antitumor activity in vitro.     

Synthesis,crystal structure,and biological activities of a Zn(II) complex with a Se substituted Schiff base

A Zn(II) complex with an organoselenium substituted Schiff base, bis{2-[(benzylimino)methyl]-4,6-dihydroselenophenol}Zn(II), has been synthesized and characterized by elemental analyses and X-ray diffraction. Zn(II) is four-coordinated by two phenolate O and two imine N from two organoselenium substituted Schiff-base ligands, forming a distorted tetrahedral geometry. The title complex and its ligand were tested in vitro for their antibacterial and antitumor activity with the complex showing higher antibacterial and antitumor activities.     

INFLUENCE OF MOLECULAR WEIGHT AND PERIODATE-MODIFICATION OF β-D-GLUCANS FROM PORIA COCOS SCLEROTIUM ON ANTITUMOR ACTIVITIES*

In this work, influence of molecular weight and periodate modification ofβ-D-glucans isolated from Poria cocos sclerotium on the antitumor activities against Sar-coma 180 and Ehrlich ascites carcinoma (EAC) tumor was studied. The results show thattwo glucans PC3 (linear β-(1→3)-D-glucan) and PC4 [β-(1→3)-D-glucan with a fewof branches and glucuronic acid] are devoid of antitumor activity. However, when theglucans were modified by periodate oxidation, borohydride reduction and mild hydrolysisor partially hydrolysis, the derivatives have obvious antitumor activities. The decreasein molecular weight of glucans after periodate modification hardly affects their antitumoractions, but on the other hand, the decrease of molecular weight without periodate modi-fication could lead to an enhancement of the antitumor activities. Moreover, the glucansand these derivatives have much higher enhancement ratios of body weight of mice thanthat of 5-Fluorouracil (5-Fu), suggesting that they are less toxic than 5-Fu.