A Facile Synthesis of Indole-based Conjugated Derivatives

A novel synthetic method was developed for the preparation of indole-based conjugated derivatives with satisfied yields. By applying this strategy, a series of new compounds were prepared conveniently. All the obtained new indole derivatives were characterized by spectroscopic analyses, giving satisfactory data corresponding to their expected molecular structures.     

Probing FtsZ and tubulin with C8-substituted GTP analogs reveals differences in their nucleotide binding sites

The cytoskeletal proteins, FtsZ and tubulin, play a pivotal role in prokaryotic cell division and eukaryotic chromosome segregation, respectively. Selective inhibitors of the GTP-dependent polymerization of FtsZ could constitute a new class of antibiotics, while several inhibitors of tubulin are widely used in antiproliferative therapy. In this work, we set out to identify selective inhibitors of FtsZ based on the structure of its natural ligand, GTP. We found that GTP analogs with small hydrophobic substituents at C8 of the nucleobase efficiently inhibit FtsZ polymerization, whereas they have an opposite effect on the polymerization of tubulin. The inhibitory activity of the GTP analogs on FtsZ polymerization allowed us to crystallize FtsZ in complex with C8-morpholino-GTP, revealing the binding mode of a GTP derivative containing a nonmodified triphosphate chain.     

Epothilone Analogues with Benzimidazole and Quinoline Side Chains: Chemical Synthesis,Antiproliferative Activity,and Interactions with Tubulin

A series of epothilone B and D analogues bearing isomeric quinoline or functionalized benzimidazole side chains has been prepared by chemical synthesis in a highly convergent manner. All analogues have been found to interact with the tubulin/microtubule system and to inhibit human cancer cell proliferation in vitro, albeit with different potencies (IC₅₀ values between 1 and 150 nM ). The affinity of quinoline‐based epothilone B and D analogues for stabilized microtubules clearly depends on the position of the N‐atom in the quinoline system, while the induction of tubulin polymerization in vitro appears to be less sensitive to N‐positioning. The potent inhibition of human cancer cell growth by epothilone analogues bearing functionalized benzimidazole side chains suggests that these systems might be conjugated with tumor‐targeting moieties to form tumor‐targeted prodrugs.     

用后功能化方法合成含吲哚二阶非线性光学发色团侧基的高分子

用后功能化方法合成了两类连有吲哚二阶非线性光学发色团侧基的高分子.通过核磁、红外、紫外-可见、示差扫描量热分析、分子量测定等手段对所得高分子进行了鉴定.此合成方法简便易行,易于产物的分离提纯,为二阶非线性光学材料的合成提供了一种新方法.     

Antitumor agents. I. DNA topoisomerase II inhibitory activity and the structural relationship of podophyllotoxin derivatives as antitumor agents.

Various podophyllotoxin derivatives from desoxypodophyllotoxin (DPT) were synthesized to examine the structural relationships between the biological significance (cytotoxic effect, effects on DNA topoisomerase II and tubulin polymerization) in vitro and antitumor activity in vivo (L 1210). An intact 6,7-methylenedioxy group of DPT is necessary to inhibit tubulin polymerization and topoisomerase II. 4'-Phenolic hydroxyl group of DPT is essential to inhibit DNA topoisomerase II and the inhibitory effect on DNA topoisomerase II contributes to a high cytotoxicity. The introduction of an aminoalkoxy group at 1-position of DPT enhances the inhibitory activity against DNA topoisomerase II and cytotoxic effect, causing the inhibitory activity against tubulin polymerization to disappear. The results of antitumor test in mice bearing L 1210 on podophyllotoxin derivatives suggest the following: 1) the strong cytotoxic effect itself is not a good indication of antitumor activity in vivo as long as it is associated with inhibition of tubulin polymerization. DNA topoisomerase II inhibitory effect contributes to an antitumor activity in vivo; 2) detailed measurements of cytotoxicity and inhibition on DNA topoisomerase II and tubulin polymerization in vitro are necessary to evaluate podophyllotoxin derivatives.     

Evolution of the total syntheses of ustiloxin natural products and their analogues

Ustiloxins A-F are antimitotic heterodetic cyclopeptides containing a 13-membered cyclic core structure with a synthetically challenging chiral tertiary alkyl-aryl ether linkage. The first total synthesis of ustiloxin D was achieved in 31 linear steps using an S(N)Ar reaction. An NOE study of this synthetic product showed that ustiloxin D existed as a single atropisomer. Subsequently, highly concise and convergent syntheses of ustiloxins D and F were developed by utilizing a newly discovered ethynyl aziridine ring-opening reaction in a longest linear sequence of 15 steps. The approach was further optimized to achieve a better macrolactamization strategy. Ustiloxins D, F, and eight analogues (14-MeO-ustiloxin D, four analogues with different amino acid residues at the C-6 position, and three (9R,10S)-epi-ustiloxin analogues) were prepared via the second-generation route. Evaluation of these compounds as inhibitors of tubulin polymerization demonstrated that variation at the C-6 position is tolerated to a certain extent. In contrast, the S configuration of the C-9 methylamino group and a free phenolic hydroxyl group are essential for inhibition of tubulin polymerization.     

New Trimethoxybenzamides and Trimethoxyphenylureas Derived from Dimethylcarbazole as Cytotoxic Agents. Part I

A convenient synthesis of novel functionalized 1,4‐dimethylcarbazole derivatives containing 3,4,5‐trimethoxybenzamido‐ureido or N‐(3,4,5‐trimethoxyphenyl)ureido group starting from their corresponding indole derivatives is reported. Three derivatives prepared ( 5g , 6c , and 6g ) were active against leukemia cell lines HL60. Both 5g and 6g showed potent antiproliferative activity against KB cell lines, likely associated with the inhibition of tubulin polymerization.     

Design,synthesis and biological evaluation of novel 2-phenyl-4,5,6,7-tetrahydro-1H-​indole derivatives as potential anticancer agents and tubulin polymerization inhibitors

A new series of 2-phenyl-4,5,6,7-tetrahydro-1H-?indole derivatives as tubulin polymerization inhibitors were synthesized and evaluated for the anti-proliferative activities. All newly prepared compounds were tested for their antiproliferative activity in vitro on the human breast cancer cell line (MCF-7) and human lung adenocarcinoma cell line (A549). Among them, compound 7b with a 4-methoxyl substituent at the phenylhydrazone moiety exhibited the most potent anticancer activity against MCF-7 and A549 with IC₅₀ values of 1.77 ± 0.37 and 3.75 ± 0.11 μM, respectively. Interestingly, 7b displayed significant selectivity in inhibiting cancer cells over LO2 (normal human liver cells). Further mechanism studies revealed that 7b significantly arrested cell cycle at G2/M phase and induced apoptosis in a dose-dependent manner. Additionally, 7b effectively inhibited tubulin polymerization with an inhibitory manner similar to that of colchicine. Furthermore, molecular docking study suggested that 7b had high binding affinities for the colchicine binding pocket of tubulin. Hence, this study demonstrates for the first time that tetrahydroindole can be used as a functional group for the design and development of new tubulin polymerization inhibitors.     

Design,synthesis, and biological evaluation of diarylpyrazole derivatives as antitumor agents targeting microtubules

A new series of novel diarylpyrazole derivatives as microtubule destabilizers were synthesized and evaluated for the anti-proliferative activities. Anti-proliferative assays were performed on the human cervix adenocarcinoma cell line (HeLa) and human gastric adenocarcinoma cell line (SGC-7901), and the compound 9s containing indole ring showed great anti-proliferative activity against HeLa cells with IC₅₀ value of 1.9 ± 0.11 μM. Further biological studies showed that 9s was able to inhibit tubulin polymerization, disrupt the cytoskeleton, block the cell cycle in the G2/M phase, and induce cell apoptosis in a concentration-dependent manner. In addition, the results of molecular docking studies showed that compound 9s could bind tightly to the colchicine binding site of tubulin through hydrogen bonding interaction. These preliminary results recommend that compound 9s is likely to be a microtubule destabilizer that deserves further investigation.     

Iridium‐Catalyzed Direct C4‐ and C7‐Selective Alkynylation of Indoles Using Sulfur‐Directing Groups

Indoles and their analogues have been one of the most ubiquitous heterocycles during the past century, and extensive studies have been conducted to establish practical synthetic methods for their derivatives. In particular, selective functionalization of the poorly reactive benzenoid core over the pyrrole ring has been a great challenge. Reported herein is an iridium‐catalyzed direct alkynylation of the indole C4‐ and C7‐positions with the assistance of sulfur directing groups. This transformation shows a wide range of functional‐group tolerance with exceptional site selectivity. The directing group can be either easily removed or transformed after catalysis. The synthetic utility of the alkyne fragment is demonstrated by the derivatization into the core structure of natural indole alkaloids.     

Synthesis and cytotoxic evaluation of cis-locked and constrained analogues of combretastatin and combretastatin A4

A series of cis-locked stilbenic compounds related to combretastatin and combretastatin A4 has been designed and synthesized. The cytotoxic effects of these rigid analogues were evaluated as well as their abilities to inhibit tubulin polymerization.     

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.     

Discovery of Novel Diarylamide N-Containing Heterocyclic Derivatives as New Tubulin Polymerization Inhibitors with Anti-Cancer Activity

Tubulin has been regarded as an attractive and successful molecular target in cancer therapy and drug discovery. Vicinal diaryl is a simple scaffold found in many colchicine site tubulin inhibitors, which is also an important pharmacophoric point of tubulin binding and anti-cancer activity. As the continuation of our research work on colchicine binding site tubulin inhibitors, we designed and synthesized a series of diarylamide N-containing heterocyclic derivatives by the combination of vicinal diaryl core and N-containing heterocyclic skeletons into one hybrid though proper linkers. Among of these compounds, compound 15b containing a 5-methoxyindole group exhibited the most potent inhibitory activity against the tested three human cancer cell lines (MGC-803, PC-3 and EC-109) with IC₅₀ values of 1.56 μM, 3.56 μM and 14.5 μM, respectively. Besides, the SARs of these compounds were preliminarily studied and summarized. The most active compound 15b produced the inhibition of tubulin polymerization in a dose-dependent manner and caused microtubule network disruption in MGC-803 cells. Therefore, compound 15b was identified as a novel tubulin polymerization inhibitor targeting the colchicine binding site. In addition, the results of molecular docking also suggested compound 15b could tightly bind into the colchicine binding site of β-tubulin.     

Synthesis of 4-substituted 3-[3-(dialkylaminomethyl)indol-1-yl]maleimides and study of their ability to inhibit protein kinase C-α, prevent development of multiple drug resistance of tumor cells and cytotoxicity

A series of 3-[3-(dialkylaminomethyl)indol-1-yl]maleimides containing the indole, dihydroindole, mercaptophenol, or tetrahydroquinoline residues at position 4 of the maleimide ring, as well as 3-(dialkylaminomethyl)indole derivatives have been synthesized. Their ability to inhibit in vitro protein kinase C-α (PKC-α) has been studied. Cytotoxicity of new compounds and their ability to constrain activation of multiple drug resistance (MDR) have been studied in the human tumor cell line. Both the toxic and the low-toxic PKC-α inhibitors prevent the activation of MDR in the tumor cells. Among compounds under study, a number of substances have been found that prevent the activation of MDR but do not inhibit PKC-α. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1977–1985, September, 2008.     

SYNTHESIS AND EVALUATION OF 2-DIAZO-3,3,3-TRIFLUOROPROPANOYL DERIVATIVES OF COLCHICINE AND PODOPHYLLOTOXIN AS PHOTOAFFINITY LABELS: REACTIVITY, PHOTOCHEMISTRY, AND TUBULIN BINDING

Derivatives of the tubulin polymerization inhibitors colchicine and podophyllotoxin bearing the photoreactive 2-diazo-3,3,3-trifluoropropanoyl (DTFP) group were synthesized for evaluation as potential photoaffinity labels of the tubulin binding site. All labels were assayed for their ability to inhibit tubulin polymerization, and N-DTFP-deacetylthiocolchicine was shown to competitively inhibit tubulin-colchicine binding with a Ki of 4-5 microM. The tubulin off-rate of this analog was similar to that of podophyllotoxin, rather than to the relatively irreversibly bound colchicine. Photochemical solvent insertion reactions of the labels were investigated. Radioactive samples of the two most active labels were prepared and used in initial protein-labeling experiments, during which the fractional occupancy of tubulin and extent of covalent incorporation were determined. A rearrangement of DTFP amides was encountered which is relevant to the utility of this moiety for use in synthesis of photoaffinity labels.     

Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa

The leaves of a tropical plant, Mitragyna speciosa KORTH (Rubiaceae), have been traditionally used as a substitute for opium. Phytochemical studies of the constituents of the plant growing in Thailand and Malaysia have led to the isolation of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids, including new natural products. The structures of the new compounds were elucidated by spectroscopic and/or synthetic methods. The potent opioid agonistic activities of mitragynine, the major constituent of this plant, and its analogues were found in in vitro and in vivo experiments and the mechanisms underlying the analgesic activity were clarified. The essential structural features of mitragynines, which differ from those of morphine and are responsible for the analgesic activity, were elucidated by pharmacological evaluation of the natural and synthetic derivatives. Among the mitragynine derivatives, 7-hydroxymitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice.     

Catalytic Asymmetric Construction of Axially Chiral Indole-Based Frameworks: An Emerging Area

Axially chiral indole-based frameworks have been recognized as a class of important five-membered heterobiaryls and developing catalytic asymmetric approaches for constructing these frameworks in an enantioselective manner is highly desirable. In recent years, synthetic chemists have paid much attention to this research field, and rapid developments have occurred. At this point, a range of axially chiral indole-based scaffolds have been constructed via various catalytic asymmetric reactions based on different strategies. Thus, the catalytic asymmetric construction of axially chiral indole-based frameworks has become an emerging area. This minireview summarizes the rapid advances in this field and gives some insights into future developments, which will help this research field to thrive.     

Recent Progress in the Development of Indole-Based Compounds Active against Malaria,Trypanosomiasis and Leishmaniasis

Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little investment in drug discovery, which is reflected in the limited available therapeutic arsenal. Authorized drugs present problems such as low efficacy in some stages of the disease or toxicity, which result in undesirable side effects and treatment abandonment. Moreover, the emergence of drug-resistant parasite strains makes necessary an even greater effort to develop safe and effective antiparasitic agents. Among the chemotypes investigated for parasitic diseases, the indole nucleus has emerged as a privileged molecular scaffold for the generation of new drug candidates. In this review, the authors provide an overview of the indole-based compounds developed against important parasitic diseases, namely malaria, trypanosomiasis and leishmaniasis, by focusing on the design, optimization and synthesis of the most relevant synthetic indole scaffolds recently reported.     

单萜吲哚生物碱Uleine及其衍生物的合成进展

生物碱uleine及其衍生物从结构上看属于单萜吲哚生物碱,它们共同的结构特征是吲哚核与碱性氮原子之间只有一个碳相隔,而不像其它单萜吲哚生物碱有两个碳原子.由于其结构特异,天然含量少,因而其合成工作一直吸引着化学工作者.总结uleine生物碱及其衍生物的合成方法,根据构建环的种类不同,把合成方法分为五类.大部分方法都是以吲哚和吡啶衍生物为起始原料进行四环的合成,有几条合成路线简短易行.