Synthesis,Profiling, and Bioactive Conformation of trans‐Cyclopropyl Epothilones

A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)?C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)?C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones.     

Design,Synthesis, and Antipoliferative Activities of Novel Substituted Imidazole-Thione Linked Benzotriazole Derivatives

A new series of benzotriazole moiety bearing substituted imidazol-2-thiones at N1 has been designed, synthesized and evaluated for in vitro anticancer activity against the different cancer cell lines MCF-7(breast cancer), HL-60 (Human promyelocytic leukemia), and HCT-116 (colon cancer). Most of the benzotriazole analogues exhibited promising antiproliferative activity against tested cancer cell lines. Among all the synthesized compounds, BI9 showed potent activity against the cancer cell lines such as MCF-7, HL-60 and HCT-116 with IC₅₀ 3.57, 0.40 and 2.63 µM, respectively. Compound BI9 was taken up for elaborate biological studies and the HL-60 cells in the cell cycle were arrested in G₂/M phase. Compound BI9 showed remarkable inhibition of tubulin polymerization with the colchicine binding site of tubulin. In addition, compound BI9 promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2. These results provide guidance for further rational development of potent tubulin polymerization inhibitors for the treatment of cancer.     

Towards a fully synthetic MUC1-based anticancer vaccine: efficient conjugation of glycopeptides with mono-, di-, and tetravalent lipopeptides using click chemistry

The membrane‐bound tumor‐associated glycoprotein MUC1 is aberrantly glycosylated in cancer cells compared with normal cells, and is therefore considered an attractive target for cancer immunotherapy. However, tumor‐associated glycopeptides from MUC1 do not elicit a sufficiently robust immune response. Therefore, antitumor vaccines were developed, which consist of MUC1 glycopeptides as the B epitopes and immune‐stimulating toll‐like receptor 2 (TLR 2) lipopeptide ligands. These fully synthetic vaccine candidates were prepared by solid‐phase synthesis of the MUC1 glycopeptides. The Pam₃Cys lipopeptide, also synthesized on solid‐phase, was C‐terminally coupled to oligovalent lysine cores, which N‐terminally incorporate O‐propargyl oligoethylene glycol acyl side chains. The MUC1 glycopeptides and lipopeptide lysine constructs were then conjugated by click chemistry to give oligovalent synthetic vaccines. Oligovalent glycopeptide–lipopeptide conjugates are considered more immunogenic than their monovalent analogues.     

Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D

The phosphonium salt 35, representing one of the two principal subunits of the epothilones, was prepared from propargyl alcohol via heptenone 22. A Wittig reaction of the phosphorane from 35 with aldehyde 33, obtained from aldol condensation of ketone 27 with aldehyde 28, afforded 37. Seco acid 42 derived from 37 underwent lactonization to give cis-9,10-dehydroepothilone D (43) which was selectively reduced with diimide to yield epothilone D (4) and, after epoxidation, epothilone B (2). An alternative route to epothilone D employed alkyne 39, obtained from 33, in a Castro-Stephens reaction with allylic bromide 34 to furnish enyne 40. The latter was semi-hydrogenated to provide 37. Alkyne 46, prepared from alcohol 45, was converted to trans-vinylstannane 47 which, in a Stille coupling with allylic chloride 50, gave 51. Seco acid 52 derived from 51 underwent lactonization to give trans-9,10-dehydroepothilone D (54). Bioassay data comparing the antiproliferative activity and tubulin polymerization of 43 and 54 with epothilone B (2), epothilone D (4), and paclitaxel (7) showed that the synthetic analogues were less potent than their natural counterparts, although both retain full antiproliferative activity against a paclitaxel-resistant cell line. No significant difference in potency was noted between cis analogue 43 and its trans isomer 54.     

Synthesis, conformational analysis, and bioassay of 9,10-didehydroepothilone D

[reaction: see text] 9,10-Didehydroepothilone D was synthesized, its conformation was studied, and its tubulin polymerization and antiproliferative activity were compared with that of epothilone D and certain analogues.     

Chemical synthesis and biological properties of pyridine epothilones

BACKGROUND: Numerous analogs of the antitumor agents epothilones A and B have been synthesized in search of better pharmacological profiles. Insights into the structure-activity relationships within the epothilone family are still needed and more potent and selective analogs of these compounds are in demand, both as biological tools and as chemotherapeutic agents, especially against drug-resistant tumors. RESULTS: A series of pyridine epothilone B analogs were designed, synthesized and screened. The synthesized compounds exhibited varying degrees of tubulin polymerization and cytotoxicity properties against a number of human cancer cell lines depending on the location of the nitrogen atom and the methyl substituent within the pyridine nucleus. CONCLUSIONS: The biological screening results in this study established the importance of the nitrogen atom at the ortho position as well as the beneficial effect of a methyl substituent at the 4- or 5-position of the pyridine ring. Two pyridine epothilone B analogs (i.e. compounds 3 and 4) possessing higher potencies against drug-resistant tumor cells than epothilone B, the most powerful of the naturally occurring epothilones, were identified.     

Synthesis and Antitumor Activity of Heterocycles Related to Carbendazim

Three types of compounds were synthesized from carbendazim ( 1 ), a benzimidazole derivative (Scheme 1 ). They included a group of esters at N1 prepared by treating carbendazim with isocyanates bearing ester groups ( 2a , 2b , 2c ), carboxyalkyl‐1,2,3,4‐tetrahydro‐s‐triazino[1,2‐a]benzimidazole‐2,4‐dione esters ( 3a and 3b , 3d and 3c derived from 3a . The antitumor potencies of the N1 esters were in the range of 7 to 40 μM, which compares favorably with carbendazim, but their water solubilities were low. The s‐triazine derivatives showed activity against pancreatic tumor cells, and one of them ( 3b ) was active in mice, but they were not effective against other tumor types. Treatment of carbendazim with 3‐bromopropionyl chloride produced 1‐methoxycarbonyl‐4‐oxo‐1,2,3,4‐tetrahydropyrimido[1,2‐a]benzimidazole ( 4 ), which gave 1‐(3‐aminopropionyl)benzimidazole 2‐methylcarbamates, substituted on the amino nitrogen ( 5a , 5b , and 5d ), when treated with amines. These products showed some antitumor activity in cell cultures, and an ethoxy derivative ( 5c ), obtained by treating 1‐methoxycarbonyl‐4‐oxo‐1,2,3,4‐tetrahydropyrimido[1,2‐a]benzimidazole with sodium ethoxide, was active in the 67–150 μM range. Some of the new compounds had good water solubility. Carbendazim kills tumor cells by inhibiting tubulin; however, s‐triazine 3b , which differs from it in size and functional groups, does not act by this mechanism.     

C6-C8 bridged epothilones: consequences of installing a conformational lock at the edge of the macrocycle

A series of conformationally restrained epothilone analogues with a short bridge between the methyl groups at C6 and C8 was designed to mimic the binding pose assigned to our recently reported EpoA-microtubule binding model. A versatile synthetic route to these bridged epothilone analogues has been successfully devised and implemented. Biological evaluation of the compounds against A2780 human ovarian cancer and PC3 prostate cancer cell lines suggested that the introduction of a bridge between C6-C8 reduced potency by 25-1000 fold in comparison with natural epothilone D. Tubulin assembly measurements indicate these bridged epothilone analogues to be mildly active, but without significant microtubule stabilization capacity. Molecular mechanics and DFT energy evaluations suggest the mild activity of the bridged epo-analogues may be due to internal conformational strain.     

Synthesis,Characterization, In Vitro Anticancer Potentiality,and Antimicrobial Activities of Novel Peptide–Glycyrrhetinic-Acid-Based Derivatives

Glycyrrhetinic acid (GA) is one of many interesting pentacyclic triterpenoids showing significant anticancer activity by triggering apoptosis in tumor cell lines. This study deals with the design and synthesis of new glycyrrhetinic acid (GA)–amino acid peptides and peptide ester derivatives. The structures of the new derivatives were established through various spectral and microanalytical data. The novel compounds were screened for their in vitro cytotoxic activity. The evaluation results showed that the new peptides produced promising cytotoxic activity against the human breast MCF-7 cancer cell line while comparing to doxorubicin. On the other hand, only compounds 3, 5, and 7 produced potent activity against human colon HCT-116 cancer cell line. The human liver cancer (HepG-2) cell line represented a higher sensitivity to peptide 7 (IC₅₀; 3.30 μg/mL), while it appeared insensitive to the rest of the tested peptides. Furthermore, compounds 1, 3, and 5 exhibited a promising safety profile against human normal skin fibroblasts cell line BJ-1. In order to investigate the mode of action, compound 5 was selected as a representative example to study its in vitro effect against the apoptotic parameters and Bax/BCL-2/p53/caspase-7/caspase-3/tubulin, and DNA fragmentation to investigate beta (TUBb). Additionally, all the new analogues were subjected to antimicrobial assay against a panel of Gram-positive and Gram-negative bacteria and the yeast candida Albicans. All the tested GA analogues 1–8 exhibited more antibacterial effect against Micrococcus Luteus than gentamicin, but they exhibited moderate antimicrobial activity against the tested bacterial and yeast strains. Molecular docking studies were also simulated for compound 5 to give better rationalization and put insight to the features of its structure.     

SAR and pH stability of cyano-substituted epothilones

[formula: see text] 3-Cyano epothilones 15-18 are the only examples of non-hydroxy C-3-substituted analogues. Their tubulin binding affinity and cytotoxicity provide meaningful structure-activity relationship information on the dependence of C-1/C-3 conformation upon activity. 12-Cyano epothilone 24 has improved pH stability over epothilone B, and its activity further supports the hypothesis that C-12 stereochemistry is not critical for tubulin affinity.     

Synthesis of Bioactive Side‐Chain Analogues of TAN‐2483B

The fungal metabolite TAN‐2483B has a 2,6‐trans‐relationship across the pyran ring of its furo[3,4‐b]pyran‐5‐one core, which has thwarted previous attempts at its synthesis. We have now developed a chiral pool approach to this core and prepared side‐chain analogues of TAN‐2483B. The synthesis relies on ring expansion of a reactive furan ring‐fused dibromocyclopropane and alkynylation of the resulting pyran. The furan ring is constructed by palladium‐catalysed carbonylative lactonisation. Various side‐chains are appended through Wittig‐type chemistry. The prepared analogues showed micromolar activity towards cancer cell lines HL‐60, 1A9 and MCF‐7 and certain human disease‐relevant kinases, including Bruton's tyrosine kinase (Btk).     

Total synthesis of hypermodified epothilone analogs with potent in vitro antitumor activity

The convergent total synthesis of hypermodified epothilone analogs 1 and 2 has been achieved with the stereoselective cyclopropanation of allylic alcohol 17 and ring-closing olefin metathesis with diene 22 as the key steps. In spite of significant structural differences between these analogs and the natural epothilone scaffold, 1 and 2 are potent inducers of tubulin polymerization and inhibit the growth of human cancer cells in vitro with sub-nM IC50 values.     

Design,Synthesis, and Biological Evaluation of 2‐(4‐Aminophenyl)benzothiazole Analogues as Antiproliferative Agents

A series of 28 novel 2‐(4‐aminophenyl)benzothiazole analogues have been synthesized and characterized using various analytical techniques like ¹H NMR, ¹³C NMR, electrospray ionization mass spectrometry, and IR and bioevaluated for their antiproliferative activity over a group of three human cancer cell lines, namely, lung cancer (A549), cervical cancer (HeLa), and breast cancer (MDA‐MB‐231), using sulforhodamine B assay method. Few synthesized molecules ( 5a , 5c , 5d , 5f , 7b , and 7j ) displayed effective growth inhibition (GI₅₀) activity against the tested human cancer cell lines at lower micromolar concentration (GI₅₀) values in the range 0.2–1.7 μM. Noticeably, compound 7b exhibited reasonable activity in all three cancer cell lines in the GI₅₀ range 0.55–1.2 μM. Further, when 7b was screened for tubulin polymerization inhibition, it exhibited more than 55% inhibition at concentration of 5.0 μM. The molecular docking simulations supported the molecular interactions of the derivatives with the targeted receptor. These derivatives may serve as lead structures for development of potential anticancer drug candidates, and 7b might act as a potential microtubule polymerization inhibitor.     

Conformational Studies on Peptides of α‐Aminoxy Acids with Functionalized Side‐Chains

Peptides of homochiral α‐aminoxy acids of nonpolar side chains can form a 1.8₈‐helix. In this paper, we report the conformational studies of α‐aminoxy peptides 1 , 2 , 3 , which have functionalized side chains, in both nonpolar and polar solvents. ¹H NMR, XRD, and FTIR absorption studies confirm the presence of the eight‐membered‐ring intramolecular hydrogen bonds (the N‐O turns) in nonpolar solvents as well as in methanol. CD studies of peptides 1 , 2 , 3 in different solvents indicate that a substantial degree of helical content is retained in methanol and acidic aqueous buffers. The introduction of functionalized side chains in α‐aminoxy peptides provides opportunities for designing biologically active peptides.     

Secondary Metabolites from the Stem Bark of Litsea akoensis and Their Cytotoxic Activity

Six new butanolides, litseadioxanins A and B ( 1 and 2 , resp.) bearing a 1,2‐dioxane moiety, litseatrinolides A and B ( 3 and 4 , resp.), and litseakolides D₁ and D₂ ( 5 and 6 , resp.), were isolated from the stem bark of Litsea akoensis, together with six known compounds. The structures of the new compounds were characterized by in‐depth NMR‐spectroscopic and mass‐spectrometric analyses. Butanolides 1 – 4 , and a mixture of 6 and litsenolide E₂, and litsenolide B₁ were tested against human tumor cells, including MCF‐7 (human breast adenocarcinoma), NCI‐H460 (non‐small‐cell lung cancer), and SF‐268 (glioblastoma) cell lines. Among the tested compounds, litsenolide B₁ exhibited marginal cytotoxic activity against MCF‐7, NCI‐H460, and SF‐268 cell lines in vitro.     

Heteroannelated (+)-muricatacin mimics: synthesis, antiproliferative properties and structure-activity relationships

Six new (+)-muricatacin mimics bearing a furano-furanone core have been synthesized and their in vitro antiproliferative activity was evaluated against a panel of human tumour cell lines. A straightforward total synthesis of (+)-muricatacin (1) from d-xylose is disclosed providing a sample of 1 that served as a positive control in antitumour assays. All new compounds showed diverse antiproliferative effects against human malignant cell lines, but were devoid of any significant cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). Additionally, the most of (+)-muricatacin analogues show selective cytotoxicities towards certain cancer cell lines, whereas only two of six analogues are broadly toxic against all cell lines under evaluation. A SAR study reveals the structural features that may be beneficial for the antiproliferative activity of these lactones. These include the absolute stereochemistry, introduction of a THF ring, interchange of the O₈ ether functionality and the C₈ methylene group in the side chain of muricatacin oxa analogues, as well as the one- or two-carbon homologation of the side chain in both 3 and 6.     

Amino acid derivatives,part 3: New peptide and glycopeptide derivatives conjugated naphthalene. Synthesis,antitumor, anti‐HIV,and BVDV evaluation

A series of peptide derivatives conjugated naphthalene residue 11–25 , the glycoside 27 as well as the 7‐glycoside 30 , and the 2‐(2‐hydroxy‐3‐(N‐benzyl‐N‐isopropylamino)propoxy)naphthalene bearing methionine 31 were synthesized. The new compounds were evaluated in vitro for cytotoxicity against HIV‐1 and bovine viral diarrhea virus (BVDV), where 31 showed remarkable activity against HIV‐1. The cytotoxicity, in vitro, of 11–25 and 27 was assayed against a panel of tumor cell lines consisting of CD4 human T‐cells containing an integrated T‐leukemia virus type 1 (HTLV‐1), CD4 human acute T‐lympho‐ blastic leukemia, splenic B‐lympho‐blastoid cells, acute B‐lymphoblastic leukemia, mela‐noma, breast adenocarcinoma, lung squamous carcinoma, hepatocellular carcinoma, prostate carcinoma, foreskin fibroblasts, and lung fibroblasts. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:576–585, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20149     

Synthesis and Antitumor Effect of Sophoridine Derivatives Bearing an Acyclic Aryloxy Phosphoramidate Mustard Functionality

To elevate the potency of sophoridine, phosphoramidate mustard motif was incorporated to D‐ring opened sophoridine scaffold. A series of acyclic aryloxy phosphoramidate mustard functionalized sophoridine derivatives were synthesized and screened for cytostatic activity in a range of different tumor cell lines (S180, H22, K562, MCF‐7, SMMC‐7721, and LoVo). All these compounds were shown to be more sensitive to S180 and H22 cells with IC₅₀ values ranging from 2.10 to 7.21 μM. In addition, all targeted derivatives distinctly are more cytotoxic to cancer cells than normal cell L929. Compounds 8b , 8c , 8d , and 8e displayed moderate tumor suppression without apparent organ toxicity in vivo against mice bearing H22 liver tumors. Their potential binding modes with DNA topoisomerase I complex have also been investigated.     

A Macrocyclic Ruthenium(III) Complex Inhibits Angiogenesis with Down‐Regulation of Vascular Endothelial Growth Factor Receptor‐2 and Suppresses Tumor Growth In Vivo

A macrocyclic ruthenium(III) complex [Ru^III(N₂O₂)Cl₂]Cl ( Ru‐1 ) is reported as an inhibitor of angiogenesis and an anti‐tumor compound. The complex is relatively non‐cytotoxic towards endothelial and cancer cell lines in vitro, but specifically inhibited the processes of angiogenic endothelial cell tube formation and cancer cell invasion. Moreover, compared with known anti‐cancer ruthenium complexes, Ru‐1 is distinct in that it suppressed the expression of vascular endothelial growth factor receptor‐2 (VEGFR2), and the associated downstream signaling that is crucial to tumor angiogenesis. In addition, in vivo studies showed that Ru‐1 inhibited angiogenesis in a zebrafish model and suppressed tumor growth in nude mice bearing cancer xenografts.     

Synthesis of substituted norbornenes and their polymerization to polynorbornenes with flexible aliphatic side‐chains

Synthesis and characterization of new thermally stable polynorbornenes functionalized with pendent flexible side‐chains are reported. The flexible side‐chains with terminal hydroxy groups were synthesized via S_NAr reactions of cyclopentadienyliron‐complexed chlorobenzenes with aliphatic diols. Condensation of these side‐chains with exo,endo‐5‐norbornene‐2‐carboxylic acid led to the formation of substituted monomers which were characterized using one‐ and two‐dimensional NMR techniques. Ring‐opening metathesis polymerization of these monomers yielded polynorbornenes with pendent side‐chains.