Synthesis and in vitro antitumor activity of asperphenamate derivatives as autophagy inducer

In an effort to improve the aqueous solubility and the antitumor activity of natural product asperphenamate, we have designed and synthesized three series of asperphenamate derivatives, including series I (simplifying molecular skeleton series), series II (introducing a hydroxyl group to A-phenyl ring series) and series III (disrupting molecular planarity series). All derivatives have displayed a significantly increased solubility compared with asperphenamate. Their growth inhibitory activities in vitro were screened by the standard MTT method in MCF-7, HeLa, and BEL-7402 cell lines. With the exception of the derivatives in series I, most of derivatives in series II and series III showed growth inhibitory activity. Among all derivatives, IM23b in series III showed the greatest potency in human breast cancer MCF-7 cells. The cellular potency of IM23b was approximately 1.5-fold more potent than that of cisplatin. The mechanism of cell death induced by IM23b in human breast cancer MCF-7 cells was further investigated. We concluded that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest.     

Testosterone propionate treatment of an XY gonadal dysgenetic chacma baboon

Behavioral studies of an XY gonadal dysgenetic chacma baboon prior to and during testosterone propionate treatment were carried out. The orchidectomized dysgenetic individual, two intact males, a castrate male, and two ovariectomized females were pair-tested with a group of eight ovariectomized stimulus females prior to and during their treatment with estradiol benzoate. Three test series were carried out. One series occurred prior to any treatment of the agonadal focal subject animals. During this series it was only the intact males who showed behavior change during their testing with the estrogen treated females. A second test series occurred after a month of daily testosterone propionate injections (1 mg/kg/day) had been given to the four agonadal subjects. During this test series the castrate male ejaculated once with one of the estrogen-treated females. All of the treated subjects showed increases in their frequency of yawning. Upon completion of this test series the androgen dosage was increased (2 mg/kg/day) and 2 weeks later a third test series was carried out. During this series the castrate male ejaculated with five of his eight estrogen-treated partners. The yawning of all the treated subjects continued. As had been the case in the second series the XY gonadal dysgenetic individual continued to behave as did the ovariectomized females. None of these animals showed any increase in any measure of male sexual behavior. This study establishes the fact that a genetic male primate deprived of in utero exposure to testicular hormones will go on to develop as a normal genetic female and will fail to exhibit increased levels of male sexual behavior during androgen treatment.     

Rational design of novel pyrrolidine derivatives as orally active neurokinin-3 receptor antagonists

The rational design of a novel series of pyrrolidine derivatives as neurokinin-3 receptor antagonists is reported starting from a selective neurokinin-1 receptor antagonist. Typical representatives in this series showed in vivo efficacy after oral administration in a NK3 mediated functional assay. This series of NK3 antagonists shows promise to deliver a novel antipsychotic.     

Plant phenological data and tree-rings as palaeoclimate indicators in south-west Finland since AD 1750

Plant phenological data and tree-rings were tested for their palaeoclimatic value in south-west Finland since AD 1750. The information from fragmentary, partly overlapping, partly non-systematically biased plant phenological records of 14 different phenomena (a total of 3,144 observations) was combined into one continuous time series of phenological indices. All site- and phenomenon-specific series were standardized to present an average of zero and standard deviation of one. The mean phenomenon-specific series were then averaged as arithmetic means for annually resolved time series representing the variability in the particular plant phenomenon. Consequently, each phenomenon-specific mean series was based on spatially normalized site-specific index series. These series were compared to each other, living-tree and subfossil tree-rings, and to early and modern meteorological time series. Phenological indices showed strong positive correlation with February to June temperatures. On the other hand, the correlations between phenological indices and precipitation data were around zero. Analysis using time-dependent running correlations showed non-stationary relationship between the tree-rings and phenological indices and observed spring temperatures. The skill of phenological data for reconstructing the spring temperatures was statistically proved.     

Bactericidal activity of magainin 2: use of lipopolysaccharide mutants

Salmonella typhimurium and a series of rough lipopolysaccharide mutants derived from it were used as target bacteria to examine the antimicrobial capacity of magainin 2. Magainin 2 demonstrated a dose-related bactericidal activity against the smooth parent strain and the series of lipopolysaccharide mutants. The lipopolysaccharide mutant series showed an ordered increase in sensitivity to the magainin 2 as the depth of the rough lesion in the lipopolysaccharide increased.     

Serial copulatory behavior of male hamsters and rats

The copulatory behavior of mammalian males is generally characterized by the male's repeated approaches to and mounting of the female. The mounting behavior can lead to intromission, and after several intromissions, an ejaculation occurs. Following ejaculation, the male refrains from sexual activity for a period of time, the so-called "post-ejaculatory interval (PEI)". Most mammals will return to copulate again. Both male hamsters and rats were used and each animal performed five series of copulations with a proestrous female. From the 1st to 5th series of copulations the hamsters showed a shorter PEI than the rats. In addition, the PEI of the hamsters showed no change after each ejaculation, while the rats gradually showed a significantly increased PEI during the five series of copulations.     

Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters

A series of Milnacipran analogs with variation in the aromatic moiety were prepared in high enantiomeric excess. Structure-activity relationships for two parallel enantiomeric series are described. The (-)-(1R,2S)-naphthyl analog (8h) showed the highest potency in the two series and is a triple reuptake inhibitor of the SERT, NET, and DAT.     

Synthesis and SAR of 6-chloro-4-fluoroalkylamino-2-heteroaryl-5-(substituted)phenylpyrimidines as anti-cancer agents

The synthesis and SAR of a series of 6-chloro-4-fluoroalkylamino-2-heteroaryl-5-(substituted)phenylpyrimidines as anti-cancer agents are described. This series of 2-heteroarylpyrimidines was developed by modifying a series of anti-tumor [1,2,4]triazolo[1,5-a]pyrimidines and 2-cyanoaminopyrimidines we reported earlier. For the 2-heteroaryl group, the best activity is obtained when the heteroaryl group has a nitrogen atom at the ortho-position to the pyrimidyl core. The structure–activity relationship for the rest of the molecule in this 2-heteroarylpyrimidine series mimics that of the [1,2,4]triazolo[1,5-a]pyrimidine series. Like triazolopyrimidines and 2-cyanoaminopyrimidines, the 2-heteroarylpyrimidines retain the capability to overcome multidrug resistance due to Pgp. Mechanism of action studies showed that the lead compounds behaved in the same manner as triazolopyrimidines and 2-cyanoaminopyrimidines. The lead compounds in this series are more potent than the corresponding triazolopyrimidines in vitro and in vivo. Compound 21 (PTI-868) showed tumor growth inhibition in several nude mouse xenograft models, and was selected to advance to preclinical development.     

Statistical analysis of fluctuations in red grouse bag data

Summary Serial correlations were performed on grouse bag data spanning periods of 40 to 100 years and taken from throughout the British Isles, to test for the presence of cyclical fluctuations. Six of the fourteen series analysed showed clear evidence of a 6-year cycle in bag numbers. Four of the remaining series produced correlograms suggestive of cycles of other lengths. Only four of the series analysed showed no evidence of cyclicity.     

Amino acid-derived piperidides as novel CCKB ligands with anxiolytic-like properties

The development of a novel series of carbamoylamino acid benzoylpiperidides as CCK_B ligands is described. Selected members of the series antagonized CCK₈-induced calcium mobilization and showed efficacy in the mouse elevated-plus maze, a measure of potential anxiolytic activity.     

Synthesis and biological evaluation of novel cytotoxic azanaphthoquinone annelated pyrrolo oximes

Two series of azanaphthoquinone annelated pyrrolo oximes have been synthesized. The antiproliferative activities of 10 compounds were evaluated on at least four different cell lines. One series of pyrrolo derivatives showed high cytotoxic activity. The effects on cell cycle and caspase activity were investigated. Compounds 9a and 9b showed an accumulation of cells in G2/M phase. Substantial and dose-dependent caspase activity was found after treatment of cells with 9a and 9b. This indicates an apoptosis inducing property of these compounds.     

杉木生长的起伏型时间序列模拟研究

起伏型时间序列法是一种新的时间序列分析法,本文介绍了起伏型时间序列林木模拟与预测方法,以杉木人工林生长为研究对象,对杉木胸径生长进行建模模拟,模拟工达到98．3％,结果令人满意,且比逐步回归法,多维时间序列分析法模拟效果更优,说明起伏型时间序列分析方法可应用于林木生长模拟与预测,从而丰富了林木生长预测与预报方法。     

Synthesis and biological activity of ferrocenyl indeno[1,2-c]isoquinolines as topoisomerase II inhibitors

Three series of indeno[1,2-c]isoquinolines bearing a ferrocenyl entity were synthesized and evaluated for DNA interaction, topoisomerase I and II inhibition, and cytotoxicity against breast human cancer cell lines. In the first and second series, the ferrocenyl scaffold was inserted as a linker between the two nitrogen atoms. In the last series, it was introduced at the end of the carbon chain. The present study showed that the ferrocenyl entity enhanced the topoisomerase II inhibition. Most compounds showed a potent growth inhibitory effect on MDA-MB-231 cell line with the IC₅₀ in μM range.     

Synthesis and biological evaluation of rhodanine derivatives as PRL-3 inhibitors

A series of rhodanine derivatives was synthesized and evaluated for their ability to inhibit PRL-3. Benzylidene rhodanine derivative showed good biological activity, while compound 5e was the most active in this series exhibiting an IC50 value of 0.9 microM in vitro and showed a reduced invasion in cell-based assay.     

Small molecules with potent osteogenic-inducing activity in osteoblast cells

A chemical screen of 45,000 compounds from a diverse collection led to the identification of two series of small molecules with potent osteogenic activity in mouse MC3T3-E1 osteoblast cells. The first chemical group was characterized by an amino benzothiazole core (AMG0892 series) and the second group by a naphthyl amide core (AMG0309 series). Using alkaline phosphatase (ALP), osteocalcin (OCL) and calcium as markers of osteoblast differentiation and mineralization, both chemical series showed EC₅₀s in the 0.01–0.2 μM range and were consistent for all three markers. Compounds inhibited cell proliferation, had no effect on apoptosis and showed evidence for CREB pathway activity. The present compounds represent some of the most potent osteogenic small molecules reported to date and provide new tools for elucidating signaling mechanisms in osteoblasts.     

Discovery and optimization of a novel series of pyrazolyltetrahydropyran N-type calcium channel (Cav 2.2) blockers for the treatment of pain

A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain.     

Benzo[c][2,7]naphthyridines as inhibitors of PDK-1

A series of substituted benzo[c][2,7]-naphthyridines were prepared and showed good potency in inhibiting PDK-1. The synthesis and SAR of this series of compounds are presented as well as the X-ray crystal structure of one of these analogs in a complex with PDK-1.     

Normal fluctuations in the earth's magnetic field influence pigeon orientation

Summary In an attempt to determine whether naturally occurring fluctuations in the earth's magnetic field influence homing pigeons' initial bearings, three series of test releases (1970, 1972, 1973) at a site 45.7 miles north of the loft were conducted under an experimental design that controlled for most extraneous variables. The mean bearings for each series showed a significant inverse correlation with the K index of magnetic activity, i.e. the bearings were more to the left when K was high. In a single series of releases at a site 43.6 miles west of the loft, the means again showed a significant inverse correlation with K. Since most of the magnetic fluctuations in all four series were less than 70 gamma, it is concluded that the sensitivity of pigeons to magnetic cues probably approaches that already demonstrated for honeybees. A brief discussion of Lamotte's (1974) paper concerning the effect of bar magnets on initial orientation is appended.     

Atmospheric teleconnection patterns associated with wheat stripe rust disease in North China

 Previous work has shown that long-term (>40 years) time series of wheat stripe rust disease from North China contain a signal related to the Southern Oscillation Index (SOI). However, no cause-and-effect relationships or direct links between SOI and disease have been established. Because mid-latitude teleconnection patterns form important links between global atmospheric variations and regional weather anomalies, such as the Southern Oscillation, studies of such patterns could result in a better physical and biological interpretation for the SOI-disease association observed previously. We used cross-spectral analyses to determine if and on which time scales severity of stripe rust in five regions of North China between 1952 and 1990 was associated with fluctuations in four Northern Hemisphere teleconnection patterns. These included the Pacific/North American, the Western Atlantic, the Western Pacific, and the Eurasian patterns. The analysis showed consistent and significant (P≤0.10) coherence relationships between the Western Atlantic (WA) pattern and stripe rust severity at a periodicity of 3.00 years. The phase relationships showed that, at the 3.00-year periodicity, the WA series and the disease series were out of phase by about half a period in all five regions. This phase difference indicated that peaks in the WA series, which are associated with below-normal winter temperatures over much of China, coincided with troughs in the disease series (i.e. low disease severity), presumably because of the negative effect of low winter temperatures on survival of the stripe rust pathogen. The analysis further showed that the WA series and the SOI series were highly significantly (P≤0.01) coherent at a periodicity of 4.33 years, which could explain the association between SOI and stripe rust severity reported previously. Received: 12 February 1997 / Accepted: 18 May 1998