Novel thiazonaphthalimides as efficient antitumor and DNA photocleaving agents: effects of intercalation, side chains, and substituent groups

A series of novel antitumor and DNA photocleaving agents was designed and synthesized by fusing a (substituted) thiazole ring to the naphthalimide skeletons. C1, the most active compound against A549, was about 30-fold more cytotoxic than the compound amonafide. A1, the most active compound against P388, was about 6-fold more cytotoxic than amonafide. C2, the most efficient DNA intercalator, showed the strongest DNA photocleaving activity via superoxide anion produced under UV light at 360 nm.     

Synthesis and antitumor activity of bithienyl-pyrimidine derivatives with electrostatic binding side chains.

A series of bithienyl-pyrimidines having cationic side chain have been developed as antitumor agents. This work illustrates the overwhelming importance of the bithienyl unit for efficient DNA binding. The X-ray structure of 4-(2',2"-thien-5-yl)2-chloropyrimidine was obtained for postulating the conformation of the bithienyl-pyrimidine moiety.     

Bisacridines with aromatic linking chains. Synthesis, DNA interaction, and antitumor activity

Synthesis of a series of bisacridine derivatives containing rigid aromatic linking chains is described. Their DNA interaction and in vitro cytotoxicity against HT-29 human carcinoma cells are reported.     

Synthesis and biological evaluation of novel 1 beta-methylcarbapenems with isothiazoloethenyl side chains

The synthesis of novel 1 beta-methylcarbapenems 1a,b bearing isothiazoloethenyl moieties at C-5 position of pyrrolidine ring and their biological evaluation are described. Both compounds showed potent and well-balanced antibacterial activity as well as high stability to DHP-I. Especially, 5-isothiazole derivative 1a exhibited excellent DHP-I stability and advanced pharmacokinetics profiles, compared to 5-isoxazole derivative 2, imipenem, and meropenem.     

Synthesis and antibacterial activity of novel ketolides with 11,12-quinoylalkyl side chains

A series of quinoylalkyl side chains was designed and synthesized, followed by introduction into ketolides by coupling with building block 6 or 32. The corresponding targets 7a–n, 33b, and 33e were tested for their in vitro activities against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed a similar antibacterial spectrum and comparable activity to telithromycin. Among them, two C2-F ketolides, compounds 33b and 33e, displayed excellent activities against macrolide-sensitive and macrolide-resistant pathogens.     

Five-member thio-heterocyclic fused naphthalimides with aminoalkyl side chains: intercalation and photocleavage to DNA

Novel five-member thio-heterocyclic fused naphthalimides with aminoalkyl side chains were designed, synthesized and evaluated. These compounds have high Scatchard binding constants. They could damage DNA (supercoiled pBR322) from form I (closed) to II (nicked) at a concentration as low as 10 microM and from form I to form III at a concentration of 50 microM. The results implied that the influence of intercalating ability of chromophores on photocleaving ability of photocleavers depended on the mechanism of photocleavage.     

Highly-efficient DNA photocleavers with long wavelength absorptions: thio-heterocyclic fused naphthalimides containing aminoalkyl side chains

Thio-heterocyclic fused naphthalimides with aminoalkyl side chains were designed, synthesized and evaluated. These compounds have long wavelength absorptions and binding affinities to Calf thymus DNA. They could photodamage supercoiled pBR322 DNA from form I (closed) to II (nicked) at a concentration as low as 0.5 microM and to form III (linear) at a concentration of 50 microM. A possible mechanism of superoxide anion was provided.     

Thio-heterocylic naphthalimides with aminoalkyl side chains: novel alternative tools for photodegradation of genomic DNA without impairment on bioactivities of proteins

Thio-heterocylic naphthalimides (R1-R5) were designed, synthesized and evaluated as nonmetallic and long-wavelength photocleavers. Some of them showed highly efficient abilities in the degradation of plasmid and genomic DNA under the mild conditions without obvious impairment on the proteins' bioactivities, when compared with frequently applied nucleic acids removal reagents or precipitants. Their differences in photodegradation selectivity to DNA rather than proteins were dependent on their photodamage mechanisms and binding modes with bio-macromolecules. When maize genomic DNA was used as substrate, 2.38 x 10(-4) M of R5 exhibited the nuclease activity of 8 Unit DNase I, R5 has some characteristic as a typical catalyst as no consumption after two cycles of the photodegradation for DNA. The experiments of enzymatic activity assay and immunology activity analysis showed that R5 was safe to proteins, suggesting its potential in the removal of transgenic material during the preparation of bioactive proteins or enzyme preparations.     

Synthesis of OSW-1 analogs with modified side chains and their antitumor activities

Four analogs of OSW-1 (1-4) with modified side chains on the steroidal skeleton were synthesized following modification of our previous route for the total synthesis of OSW-1. Testing of the analogs against growth of tumor cells demonstrated that the 22-one function and the full length of the side chain of OSW-1 were not required for the antitumor action of OSW-1.     

Synthesis and anthelmintic activity of cyclohexadepsipeptides with cyclohexylmethyl side chains

Cyclohexadepsipeptides (CHDPs) with cyclohexylmethyl side chains represent novel enniatins with in vivo activity against the parasitic nematode Haemonchus contortus Rudolphi in sheep. It was found that the replacement of benzylic by cyclohexylmethyl side chains on the enniatin skeleton can increase anthelmintic efficacy. Here we report on a simple total synthesis of the precursors for this type of CHDPs and an efficient chemical transformation of the benzylic into the corresponding cyclohexylmethyl side chains.     

Synthesis and in vitro antitumor activity of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains

A series of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains were synthesized and tested for their in vitro antitumor activity against human myelogenous leukemia K562 cells. Among them, (3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)methyl 4-(4-fluorophenyl)piperazine-1-carbodithioate 8q exhibited significant inhibitory activity against K562 cells with IC(50) value of 0.5 microM.     

Design,synthesis, and biological activity evaluation of a series of pleuromutilin derivatives with novel C14 side chains

In this work, according to the ‘me-too me-better’ design strategy, a peculiar side chain different from lefamulin at C14 position of pleuromutilin was introduced. A series of novel thioether pleuromutilin derivatives containing cyclohexane in the C14 chain was synthesized by ten-step synthesis reaction. All derivatives were characterized by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometer (HRMS). Furthermore, majority of derivatives displayed moderate antibacterial activity in vitro. However, the compound 2C and 2J exhibited comparable or superior antibacterial activity to lefamulin. The summarized structure-activity relationship not only made the variety of pleuromutilin derivatives more diverse, but also provided new ideas for its design and development.     

Synthesis of brassinosteroids of varying acyl side chains and evaluation of their brassinolide-like activity

Brassinosteroids containing various side chain moieties were synthesized and their activity was determined as the reciprocal logarithm of the ED(50) (50% effective dose per plant in moles) in the rice lamina inclination assay using synergist indole-3-acetic acid (IAA). The introduction of a hydroxyl group in the alpha-position to the carbonyl group of the ester structure significantly enhanced the activity. 2alpha,3alpha-Dihydroxy-17beta-[(2R,3S)-2-hydroxy-3-methylpentanoyl]oxy-B-homo-7-oxa-5alpha-androstan-6-one showed the highest activity, for which the pED(50) was determined to be 10.5 under synergistic conditions with IAA. Under identical conditions, the pED(50) values of brassinolide and castasterone were determined to be 13.6 and 12.3 respectively. With respect to the alpha-carbon of the acyl moiety, the R-form was 10 times more potent than the corresponding S-form. Substituting the terminal structure (Et) of the side chain to that of the most potent compound, brassinolide (i-Pr), did not increase the activity.     

Naphthalimide intercalators with chiral amino side chains: effects of chirality on DNA binding, photodamage and antitumor cytotoxicity

Several novel heterocyclic-fused naphthalimides intercalators with chiral amino side chains were investigated. Their side chains' chiral configuration determines DNA binding activities in the order: S-enantiomers > R-enantiomers. And their DNA photodamaging activities were in good agreement with their DNA binding constants, the S-enantiomers could photocleave circular supercoiled pBR322 DNA more efficiently than their R-enantiomers. S-enantiomer B(3) could photodamage DNA at 0.2 microM and cleave supercoiled plasmid DNA from form I to form II completely at 50 microM. Almost all of these intercalators showed effective cytoxicities against human lung cancer cells and murine leukemia cells. S-enantiomers showed different antitumor cytotoxicity by comparison with R-enantiomers. This work may provide additional information for the role of amino side chains on intercalators as antitumor agents.     

Synthesis and antitumor activity of novel paclitaxel-chlorambucil hybrids

The syntheses and antitumor activity of three paclitaxel-chlorambucil hybrids are presented. Hybrid 3 showed significant in vivo efficacy.     

Synthesis and evaluation of antitumor activity of novel N-acyllavendamycin analogues and quinoline-5,8-diones

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.     

Design, synthesis, and evaluation of N-aroyloxy-2-thiopyridones as DNA photocleaving reagents.

N-Benzoyloxy-2-thiopyridone (12) was shown to induce single-strand nicks in duplex DNA upon irradiation with visible light (lambda&350 nm). This finding led to the design of a series of compounds, in which an acridinyl nucleus was covalently linked to the N-benzoyloxy-2-thiopyridone unit. These conjugates (15, 16, 17 and 18) were synthesized and evaluated as novel DNA photocleaving reagents. Optimal photocleaving activity was observed for conjugate 16, in which a flexible polymethylene spacer of 4 carbons was used to connect the aminoacridine entity to the thiopyridone. This compound was shown to cleave DNA at low microM concentrations and was approximately two-orders of magnitude more efficient than the parent N-benzoyloxy-2-thiopyridone (12). Furthermore, the DNA cleavage ladders induced by 16 and 12 were found to be identical and of no significant sequence selectivity. These data suggest that the N-aroyloxy-2-thiopyridones can be used for the design of new DNA photocleaving reagents with potential use as 'photofootprinting agents' or as 'site-directed photonucleases'.     

Synthesis and anti-influenza activity of aminoalkyl rupestonates

A series of aminoalkyl rupestonates were designed and synthesized by reacting rupestonic acid with 1,ω-dibromoalkanes, followed by amination. All of the new compounds were bioassayed in vitro to determine their activities against influenza A (H3N2, H1N1) and B viruses. The results showed that compounds 5a-5g, which each contain a 1H-1,2,4-triazolyl moiety, were found to be the most potent set of compounds. Compound 5g was demonstrated to possess the highest inhibitory activity against influenza H3N2 and H1N1, with IC(50) values of 0.97 and 0.42 μM, respectively. Our results also indicated that compounds 2g, 3g, 4g and 5g, which contain ten-CH(2)-unit spacers between the rupestonic acid and amino functional groups, were the most potent inhibitors of influenza H1N1 among the synthesized compounds. Unfortunately, most of the synthesized compounds did not show an obvious activity against influenza B; the only exceptions were compounds 5d and 5f, which had IC(50) values of 17.3 and 3.2 μM, respectively. Compounds 4g and 5g were potent inhibitors of influenza H1N1, and they might be potentially developed as new lead anti-influenza virus compounds. Further studies of the mechanism of action are underway.     

Synthesis and antitumor activity of novel 20s-camptothecin analogues

In an effort to decrease the toxicity and improve the stability of labile lactone ring of camptothecin, nitrogenous heterocyclic aromatic groups were introduced into 20-position of camptothecin and seventeen new 20s-camptothecin derivatives were obtained in quantitative yield. The cytotoxicity in vitro on three cancer cell lines and the stability of the lactone in phosphate-buffered solution (PBS) of these derivatives were evaluated. Most of these tested derivatives possessed better cytotoxicity than topotecan. Analogues 6, 12 exhibited the best antitumor activity in vivo in all derivatives we prepared. The results suggested that introduction of pyrazole in 10- or 20-position of camptothecin could promote antitumor activity in vitro and in vivo, simultaneously bring much increase of the stability of lactone.     

The contribution of side chains to antitumor activity of a polysaccharide from Codonopsis pilosula

In order to assess the potential contribution of the side chains of a polysaccharide (CPPW1) from the roots of Codonopsis pilosula to the biological activities, we chose CPPW1 and its backbone (CPPW1B) as the research targets to compare them with their antitumor and immunomodulatory activity. The results demonstrated CPPW1 could significantly inhibit the tumor growth of H22-bearing mice and simulate lymphocyte proliferation. Meanwhile the phagocytic capability of macrophages and NO production were also enhanced. However, CPPW1B could only inhibit the tumor weight and did not work to immune system at all. Additionally, both CPPW1 and CPPW1B had no toxicity in vivo. Taken together with all data, we found the sugar side chains attached to the backbone of CPPW1 played a pivotal role in fighting against tumor and activating immune system.