We synthesized a series of enediyne containing Combretastatin A-4 analogues and evaluated the growth inhibitory activity of analogues against two human hepatoma cell lines (Hep G2, Hep 3B), two breast cancer cell lines (MDA-MB-231, MCF-7) and human lung cancer cell line (A-549). It was found that compounds 39a, 39d, 39e, 39f and 40a produced growth inhibitory activity for the five human cancer cell lines. Among them, compound 40a showed the best inhibitory activity (IC50 = 0.8 £gM for A-549 and IC50 = 8.53 £gM for Hep 3B) which were comparable to the Combretastatin A-4 (IC50 = 1.57 £gM for A-549 and IC50 = 14.32 £gM for Hep 3B).

A total of 27 new enediyne analogs of combretastatin A-4 (CA-4), with different substituents (Cl, Br, OCH3, SCH3 or N(CH3)2 ) of the aryl A-ring, were designed, synthesized, and evaluated for their growth inhibition activity against human tumor cell lines. Among them, compound 14a showed most significant inhibition activity against Hep3B (0.22 £gM), A-549 (0.49 £gM) and MCF-7 (0.22 £gM), and these activities were greater than CA-4. The enediyne analog 14a may be consider as a new drug candidate worthy of further investigation and development as a potential antitumor agent.

No description available.

We designed a new series of enediyne and their derivatives, and evaluating for their growth inhibition activity against human tumor cell lines. This dissertation is composed of two parts. First, compounds 6c, 6e, 6g and 7g displayed good growth inhibition activity against A549 (non-small-cell lung cancer), AGS (human stomach adenocarcinoma), PC-3 (prostate cancer), BT483 (breast carcinomas), HeLa (human cervical epithelioid carcinoma), OVCA (ovarian cancer cell line), SKHep (hepatocellular carcinoma), H460 (human lung cancer cell line) and SW620 (Human Colorectal Cancer Cell Line), especially compound 7g is better, and its average IC50 is 8.79£gM. Second, compounds 25a and 26 displayed better growth inhibition activity against HeLa (human cervical epithelioid carcinoma), OVCA (ovarian cancer cell line), AGS (human stomach adenocarcinoma) and H460 (human lung cancer cell line), and their average IC50 are10.82 and 11.08 £gM.

A series of anilines and enediynes containing Combretastatin A-4 analogues were synthesized. The growth inhibitory activity of these analogues were evaluated against three human cancer cell lines including human hepatoma (Hep G2), breast cancer (MBA-MB231) and lung cancer (A-549) cell lines. The IC50 values of the synthesized compounds are between 10-5-10-7 £gM. We found that compounds 11e, 12e and 13e were observed good growth inhibitory activity for the three human cancer cell lines, especially for A549 (IC50 = 0.22, 0.40 and 0.16 £gM respectively).

Thesis advisor: Steven D. Bruner / The enediyne antitumor antibiotics are produced by complex biosynthetic machinery in acetomycetes. This dissertation will focus on the study of three enzymes involved in key steps in the biosynthesis of two enediynes, neocarzinostatin and C-1027. Neocarzinostatin is biosynthesized by a number of enzymes that synthesize and decorate the enediyne core and the peripheral moieties. NcsB1 is one enzyme involved in functionalizing the naphthoic acid portion of neocarzinostatin, a key group involved in binding to target DNA duplexes. The enzyme has been shown to be a promiscuous (<italic>S</italic>)-adenosylmethionine-dependent <italic>O</italic>-methyltransferase responsible for methylating a variety of hydroxynaphthoic acids. Multiple crystal structures of NcsB1 cocomplexed to substrate and/or cofactor have been solved. These structures revealed a displacement of the C-terminal domain when not bound to substrate, a movement that likely opens up the active site for naphthoate binding. Additionally, the ternary complex structure of 1,4-dihydroxynaphthoic acid, (<italic>S</italic>)-adenosylhomocysteine, and NcsB1 was solved and showed a rotation of this alternate substrate in the binding pocket, allowing for methylation. These results led us to probe NcsB1 activity using active site mutants, demonstrating altered substrate specificity and revealing key residues in substrate binding. The final step of neocarzinostatin biosynthesis involves multiple enzymes that convergently assemble the multiple biosynthetic intermediates to form the chromophore. NcsB2, originally proposed to catalyze the attachment of the naphthoic acid moiety to the enediyne core, has been characterized <italic>in vitro</italic>. Studies into its substrate specificity as an adenylation domain led to a revised biosynthetic pathway of 2-hydroxy-7-methoxy-5-methyl naphthoic acid. Instead of catalyzing the attachment of an enzyme bound naphthoic acid to the enediyne core, NcsB2 was found to act as a CoA-ligase, activating a variety of naphthoic acids and forming a naphthoyl-CoA intermediate. The results of these studies present an outstanding opportunity to produce novel analogs of neocarzinostatin by manipulating its biosynthesis. C-1027 is an architecturally similar enediyne that is also biosynthesized in a convergent route. C-1027 is a member of a class of enediynes that contains a functionalized &beta;-tyrosine derived from L-tyrosine. The first catalytic step towards this beta-tyrosine moiety is achieved by <italic>Sg</italic>TAM, a tyrosine aminomutase that catalyzes a 2,3-amino shift on L-tyrosine to form (<italic>S</italic>)-&beta;-tyrosine. The first X-ray crystal structure of <italic>Sg</italic>TAM was recently solved by our group, revealing structural homology to ammonia lyases. Through site-directed mutagenesis, X-ray crystallography, and biochemical analysis, residues that influence the mechanism by which <italic>Sg</italic>TAM catalyzes this difficult transformation were explored. From these studies, the enzymatic base and other pertinent residues involved in catalysis have been identified. In addition, residues that close the tunnel leading to the active site, thought to play a key role in mutase activity, were probed. Further study of rational mutants of <italic>Sg</italic>TAM will allow us to engineer its activity to alter its substrate specificity and the type of product it produces. / Thesis (PhD) — Boston College, 2009. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

No description available.

Gold catalysts have the characteristic of promoting nucleophilic reaction. The cyclization reaction of enediynes catalyzed by gold activated by silver in toluene at 100oC to give 6H-dibenzo[c,h]chromen-6-ones (63), 6H-benzo[c]chromen-6-one (66) and Arnottin I (10) is described. Treatment of enediynes (61¡B65) with 5 mol% of Ph3PAuCl and 10 mol% of AgSbF6 in toluene at 100oC gave 6H-dibenzo[c,h]chromen-6-ones (63) and 6H-benzo[c]chromen-6-one (66) in good yield. In addition to using gold catalyst, electrophilic reagents employed in the reaction caused one cyclization instead of two cyclization. Furthemore, a mechanistic study and GC-MS data showed that the toluene could participate in the reaction. Enediynes (73) can be synthesized by a series of organic synthesis with few steps. Treatment of enediynes (73) with 5 mol% of Ph3PAuCl and 10 mol% of AgSbF6 in toluene at 100oC gave natural product-Arnottin I (10).

Small-molecule DNA interactive compounds are critical as both carcinogens and therapeutic agents. In this research, a synthetic precursor to a known carcinogen, (±)-N’-nitrosonicotine-5’-acetate was synthesized, and its interactions with DNA were evaluated by polyacrylamide gel electrophoresis and electrospray-ionization mass spectrometry. A library of skipped benzimidazolium aza-enediynes which selectively target unmethylated cytosines in presence of unmethylated cytosines were synthesized, and their biological properties were evaluated in a nicking assay and cytotoxicity study. Finally, a series of structural analogs to a antineoplastic agent, UK-1, were synthesized via a biaryl coupling at C2 on the benzoxazole. / text

Carbohydrates represent a keystone among biological molecules. Well known as a source of energy, sugars also form the backbone of various biopolymers, act as markers and receptors for cellular communication and modulate lipid and protein functions. As such a powerful class, carbohydrates represent a useful pool from which both nature and man have drawn structures to produce biologically active compounds with a variety of modes of action. Beyond their importance to biology, sugars have represented attractive synthetic targets to chemists given their densely functionalized scaffolds. The work presented in this thesis aims to employ synthetic chemistry to provide both natural and designed carbohydrates in order to carry out biological studies to improve our understanding of these compounds' particular effects. In the first part, a synthesis is developed for the carboline disaccharide domain of the cytotoxic enediyne, shishijimicin A. The route employs a Reetz-Müller-Starke reaction to install the domain's quaternary center, with addition of a carboline dianion to complete the target. Iminosugars represent the focus of the second portion of the thesis. These polyhydroxylated alkaloids have long been investigated for their ability to mimic single sugars, inhibiting various glycosidases and glycosyltransferases. The endocyclic nitrogen atom of members of this class can act as a functional handle for alkylation, with increased chain length increasing both potency of enzyme inhibition and toxicity in cellula. Specific iminopyranose structures with D-gluco stereochemistry have broad-spectrum antiviral activity, while those with D-galacto stereochemistry are antiviral with respect to hepatitis C, but not other genetically related viruses. Reported herein are syntheses of classes of iminosugars to determine the influence of both N-alkylation chain length and iminopyranose stereochemistry on the spectrum of antiviral activity. Complementing antiviral activity with isolated enzyme inhibition assays, the work aims to identify new targets for next generation antivirals. Finally, the prototypical iminosugar, D-deoxynojirimycin, is conjugated to a second natural product, D-&alpha;-tocopherol. By replacing the more common normal alkyl group with a lipid, the goal was to reduce cellular toxicity, while also taking advantage of the natural active transport for the lipid to increase uptake of the drug. Surprisingly, this change provided a marked shift in selectivity of enzyme inhibition and antiviral ability. In order to fully characterize the mechanism, the mentioned enzymatic and antiviral studies were supplemented with lipidomic, STED-microscopy and pharmacokinetic investigations.