Novel non-benzimidazole chk2 kinase inhibitors

In a recent paper, [Arienti, K. L.; Brunmark, A.; Axe, F. U.; McClure, K. M.; Lee, A.; Blevitt, J.; Neff, D. K.; Huang, L.; Crawford, S.; Chennagiri, R. P.; Karlsson, L.; Brietenbucher, J. G. J. Med. Chem.2005, 48, 1873], we described the discovery of a class of benzimidazole chk2 kinase inhibitors, exemplified by compound 1, which had radio-protective effects in human T-cells subjected to ionizing radiation. Here, a series of non-benzimidazole analogs intended to define the scope of the SAR about this new series of inhibitor, and allow for refinement of the binding model of these compounds to the chk2 kinase is described.     

Synthesis,resolution, and determination of the absolute configuration of the enantiomers of cis-4,5-dihydroxy-1,2-dithiane 1,1-dioxide,an HIV-1NCp7 inhibitor

The anti-HIV activity of (+/-)-cis-4,5-dihydroxy-1,2-dithiane 1,1-dioxide [(+/-)-cis-1,1-dioxo-[1,2]-dithiane-4,5-diol, NSC-624151] and its attack on the zinc finger domain of the HIV-1 nucleocapsid p7 (NCp7) protein has been established [Rice, W. G.; Baker, D. C.; Schaeffer, C. A.; Graham, L.; Bu, M.; Terpening, S.; Clanton, D.; Schultz, R.; Bader, J. P.; Buckheit, R. W.; Field, L.; Singh, P. K. Turpin, J. A. Antimicrob. Agents Chemother. 1997, 41, 419]. In order to determine which enantiomer of NSC-624151 is the more active component, the compound was resolved via its bis-'Mosher ester', which was prepared via its reaction with two equiv of (-)-(R)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride. The diastereoisomeric esters were separated, and each ester was hydrolyzed to yield enantiomers with (D)(21) +151 degrees (c 0.5, MeOH) and (D)(21) -146 degrees (c 0.5, MeOH). Single-crystal X-ray analysis of the (-)-bis-'Mosher ester' showed that the (-)-enantiomer is the (4S, 5R)-compound. The (-)-enantiomer (NSC 693195) was ca. twice as active (EC(50) 8.8+/-0.2 microM) as its (+)-counterpart (NSC 693194) (EC(50) 16.2+/-2.4 microM) in the XTT assay against HIV-1. All three compounds were found to be approximately equally effective in promoting Zn ejection from the NCp7 zinc finger. As the more anti-HIV active enantiomer is only slightly more active than the racemic form, it appears to offer no advantages over the racemic form.     

BUCHBESPRECHUNGEN

Book reviewed in this article:
reviews type of article–
M ason , J. L. (ed.): Evolution of domesticated animals . London, New York: Longman 1984.
G riffiths , G. C. D. (ed.): Flies of the Nearctic Region . Vol. VIII: Cyclorrhapha II (Schizophora: Calyptratae), Part 2 Anthomyiidae, Number 1 by G. C. D. G riffiths . Stuttgart: E. Schweitzerbart'sche Verlagsbuchhandlung 1982.
S impson , G. G.: Penguins . Past and Present, Here and There. New Haven and London: Yale University Press 1983.
G ans , E.; P ouch , F. H. (eds.): Biology of the Reptilia . Vol. 12. New York – London: Academic Press 1982. 564 S. DM 353,–. G ans , E. (ed.):
M atsuno , K.; D ose , K.; H arada , K.; R ohlfing , D. L. (eds.): Molecular Evolution and Protobiology . New York, London
F elsenstein , J. (ed.): Numerical Taxonomy . Nato AS1 Series. Series G Ecological Sciencesxs
S meets , W. J. A. J.; N ieuwenhuys , R.; R oberts , B. L.: The Central Nervous System of Cartilaginous Fishes . Structure and Functional Correlations. Berlin, Heidelberg, New York: Springer 1983
H echt , M. K.; W allace , B.; P range , G. T. (eds.): Evolutionary Biology . Vol. 18. New York and London     

Structure–activity relationships and in vivo activity of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor

Structure–activity relationships (SAR) of analogues of lead compound 1 were investigated and compound 16 was selected for further study in animal models of pain. Compound 16 was shown to be a potent antihyperalgesic agent in both the rat acute complete Freund’s adjuvant (CFA) model of inflammatory pain [Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. rain Res. 1988, 455, 205] and the knee joint model of chronic inflammatory pain [Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.; Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks, G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain 2006, 10, 537].     

BUCHBESPRECHUNGEN

T uck , G. S.; H einzel , H.: Die Meeresvögel der Welt. Ein Taschenbuch für Ornithologen und Naturf reunde. Aus dem Englischen übers. u. bearb. von E lisabeth und Dr. H. G oethe
K nussmann , R.: Vergleichende Biologie des Menschen
K aestner , A. (Begründer): Lehrbuch der speziellen Zoologie. Band I: Wirbellose Tiere. Herausgegeben von H ans -E ckhard G runer
H eberer , G.: Allgemeine Abstammungslehre. 2., neu bearb. und erweit. Aufl. von B. Z epernick
M oore , W. J.: The Mammalian Skull. Biological Structure and Function 8
R andall , D. J.; B urggren , W. W.; F arrell , A. P.; H aswell , M. S.: The evolution of air breathing in vertebrates
S auer , H. W.: Entwicklungsbiologie. Ansätze zu einer Synthese. Mit einem Geleitwort vonF. S eidel . Hochschultext
H ardisty , M. W.: Biology of the Cyclostomes. (Biologie der Cyclostomen). London: Chapman and Hall 1979. XIV, 428 S., zahlreiche Abb., graph
W eick , F.: Die Greifvögel der Welt. Ein farbiger Führer zur Bestimmung der Ordnung Fakoniformes. Unter Mitarbeit von L. H. B rown , Karen, Kenia. Hamburg und Berlin
A pfelbach , R.; D öhl , J.: Verhaltensforschung. 3., neubearb. u. erw. Aufl
H ennig , W illi : Phylogenetische Systematik. Hrsg. Prof. Dr. W olfgang H ennig
K ämpfe , L.; K ittel , R.; K lapperstück , J.: Leitfaden der Anatomie der Wirbeltiere. 4.,überarb     

BUCHBESPRECHUNGEN

Book reviewed in this article: Schneider , H.: Hypothese, Experiment, Theorie. Zum Selbstverständnis der Naturwissenschaft. Krsi? , R. V.: Die Gewebe des Menschen und der Säugetiere. Ein Atlas zum Studium für Mediziner und Biologen. Cardozo , A.: Bibliografia de los Camelidos Sudamericanos. Chivers , D. J.; Joysey , K. A. (Eds.): Recent Advances in Primatology. Senglaub , K.: Wildhunde Haushunde. Mit 40 Farbtafeln von Reiner Zieger . Evolution of Insect Migration and Diapause. Ed. H. Dingle . With contributions by H. Dingle , M. H. Hoy , C. A. Istock , J. Lumme , S. Masaki , R. C. Rainey , M. A. Rankin , C. Solbreck , T. R. E. Southwood , C. A. Tauber , M. J. Tauber , K. Vepsäläinen , G. P. Waldbauer . Higgins , L. G.; Riley , N. D.: Die Tagfalter Europas und Nordafrikas. Ein Taschenbuch für Biologen und Naturfreunde. Übers. u. bearb. von W. Forster . 2. neubearb. und ergänzte Auflage. Sambraus , H. H. (Hrsg.): Nutztierethologie. Das Verhalten landwirtschaftlicher Nutztiere. Eine angewandte Verhaltenskunde für die Praxis. Unter Mitarbeit von H. Brummer ; G. van Putten ; M. Schäfer ; G. Wennrich. Apfelbach , R.; Döhl , J.: Verhaltensforschung. Eine Einführung. Limnofauna Europaea. Ed. by J. Illies . Peters , G.: Vergleichende Untersuchungen zur Lautgebung einiger Feliden (Mammalia, Felidae). Myriapoda. III. Internationaler Kongreß für Myriapodologie, Hamburg, 3.-9. April 1975. Editor: Prof. Dr. Otto Kraus . Brodal , A.; Hild , W.; Limborgh , J. van ; Ortmann , R.; Schiebler , T. H.; Töndury , G.; Wolff , E. (Eds.): Advances in Anatomy, Embryology and Cell Biology. Vol. 54, Part 6: Internal Ear Angioarchitectonic of Serpents. By M. Lüdicke . Precht , W.: Neuronal Operations in the Vestibular System. Piiper , J. (Ed.): Proceedings in Life Sciences. Handbook of Sensory Physiology. Ed. Board: H. Autrum , R. Jung , W. R. Loewenstein , D. M. Mac Kay and H. L. Teuber . Vol. 7, Part 5: The Visual System in vertebrates. By A. Hughes , F. Crescitelli , D. J. Eder , A. M. Granada , D. I. Hamasaki , K. Holmberg , N. A. Locket , W. N. Mc Farland , D. B. Meyer and W. R. A. Muntz . Ed. by F. Crescitelli . Bateson , P. P. G.; Klopfer , P. H. (Eds.)     

Book Reviews

Zoophysiology. Coordinating Editor: F arner , D. S. Editors: H einrich , B.; H oar , W. S.; J ohansen , K.; L anger , H.; N euweiler , G.; R andall , D. J. Vol. 17: S mith , R. J. F.: The Control of Fish Migration. .
Systematische Zoologie. Begründet von A dolf R emane , V olker S torch und U lrich W elsch . Fortgeführt von Prof. Dr. V olker S torch , Zoologisches Institut der Universität Heidelberg, und Prof. Dr. Dr. U lrich W elsch , Anatomische Anstalt der Universität München.     

Glu375Gln and Asp225Val mutants: about the nature of the covalent linkages between heme group and apo-Protein in bovine lactoperoxidase

In analogy with studies previously reported for myeloperoxidase (Kooter, I. M.; Moguilevsky, N.; Bollen, A.; Van der Veen, L. A.; Otto, C.; Dekker, H. L.; Wever, R. J. Biol. Chem. 1999, 274, 26794), we examined for bovine lactoperoxidase the effect of mutation of Asp225 and Glu375, the residues thought to be responsible for the covalent binding of the heme group to the apoprotein. Starting from the plasmid encoding rbLPO (Watanabe, S.; Varsalona, F.; Yoo, Y.; Guillaume, J. P.; Bollen, A.; Shimazaki, K.; Moguilevsky, N. FEBS Letters 1998, 441, 476), which was engineered to carry mutations in correspondence of those residues, the mutants Asp225Val and Glu375Gln were expressed in CHO cells and their products purified and characterized. Unequivocal evidence about the existence of ester linkages as well as their relative contribution to the specific spectroscopic and catalytic properties of bLPO is here discussed.     

Hydantoin derivative formation from oxidation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) and incorporation of 14C-labeled 8-oxodG into the DNA of human breast cancer cells

One-electron oxidation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) yielded a guanidinohydantoin derivative (dGh) and a spiroiminodihydantoin derivative (dSp), both putatively mutagenic products that may be formed in vivo. The nucleoside dGh was the major product at room temperature, regardless of pH. The results are contrary to previously published model studies using 2',3',5'-triacetoxy-8-oxo-7,8-dihydroguanosine (Luo, W.; Miller, J. G.; Rachlin, E. M.; Burrows, C. J. Org. Lett. 2000, 2, 613; Luo, W.; Miller, J.G.; Rachlin, E.M.; Burrows, C.J. Chem. Res. Toxicol. 2001, 14, 927), who observed a spiroiminodihydantoin derivative as the major product at neutral pH. Clearly, the functional groups attached to the ribose moiety of 8-oxodG influence the oxidation chemistry of the nucleobase derivative. To explore this chemistry in vivo, (14)C-labeled 8-oxodG was synthesized and incubated with growing MCF-7 human breast cancer cells, resulting in the incorporation of the compound into cellular DNA as measured by a novel accelerator mass spectrometry assay.     

Identification of new Cdc25 dual specificity phosphatase inhibitors in a targeted small molecule array

Dual specificity protein phosphatases (DSPases) are key regulators of signal transduction, oncogenesis and the cell cycle. Few potent or specific inhibitors of DSPases, however, are readily available for these pharmacological targets. We have used a combinatorial/parallel synthetic approach to rigidify the variable core region and modify the side chains of 4-(benzyl-(2-[2,5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)- 2-decanoylamino butyric acid (or SC-alphaalphadelta9), which is the most active element in a previously described library of phosphatase inhibitors (Rice, R. L.; Rusnak, J. M.; Yokokawa, F.; Yokokawa, S.; Messner, D. J.; Boynton, A. L.; Wipf, P.; Lazo, J. S. Biochemistry 1997, 36, 15965). Several analogues were identified as effective inhibitors of the protein tyrosine phosphatase (PTPase) PTP1B and the DSPases VHR and Cdc25B2. Two compounds, FY3-alphaalpha09 and FY21-alphaalpha09, were partial competitive inhibitors of Cdc25B2 with Ki values of 7.6+/-0.5 and 1.6+/-0.2 microM, respectively. FY21-alphaalpha09 possessed only moderate activity against PTP1B. Consistent with its in vitro anti-phosphatase activity, FY21-alphaalpha09 inhibited growth in MDA-MB-231 and MCF-7 human breast cancer cell lines. FY21-alphaalpha09 also inhibited the G2/M transition in tsFT210 cells, consistent with Cdc25B inhibition. Several architectural requirements for DSPase inhibition were revealed through modification of the side chain moieties or variable core region of the pharmacophore, which resulted in decreased compound potency. The structure of FY21-alphaalpha09 provides a useful platform from which additional potent and more highly selective phosphatase inhibitors might be generated.     

BUCHBESPRECHUNGEN

S tephan , H.; B aron , G.; F rahm , H. D.: Comparative Brain Research in Mammals.
S uzuki , D. T.; G riffiths , A. J. F.; M iller , J. H.; L ewontin , R. C.: G enetik. Übersetzt von S. A chten und P. B öhm .
K ämpfe , L othar (ed.): Evolution und Stammesgeschichte der Organismen. Bearbeitet von 5 Fachwissenschaftlem. 3., neubearbeitete und erweiterte Auflage.     

The design and synthesis of a potent Angiotensin II cyclic analogue confirms the ring cluster receptor conformation of the hormone Angiotensin II

The novel amide linked Angiotensin II potent cyclic analogue, c-[Sar1,Lys3,Glu5] ANG II 19 has been designed and synthesized in an attempt to test the aromatic ring clustering and the charge relay bioactive conformation we have recently suggested for ANG II. This constrained cyclic analogue was synthesized by connecting the Lys3 amino and Glu5 carboxyl side chain groups, and it was found to be potent in the rat uterus assay and in anesthetized rabbits. The central part of the molecule is fixed covalently in the conformation predicted according to the backbone bend conformational model proposed for Angiotensin II. The obtained results using a combination of 2D NMR, 1D NOE spectroscopy and molecular modeling revealed a similar Tyr4-Ile5-His6 bend, a His6-Pro7 trans configuration and a side chain aromatic ring cluster of the key aminoacids Tyr4, His6, Phe8 for c-[Sar1,Lys3,Glu5] ANG II as it has been found for ANG II (Matsoukas, J. H.; Hondrelis, J.; Keramida, M.; Mavromoustakos, T.; Markriyannis, A.; Yamdagni, R.; Wu, Q.; Moore, G. J. J. Biol. Chem. 1994, 269, 5303). Previous study of the conformational properties of the Angiotensin II type I antagonist [Hser(gamma-OMe)8] ANG II (Matsoukas, J. M.; Agelis, G.; Wahhab, A.; Hondrelis, J.; Panagiotopoulos. D.; Yamdagni, R.; Wu, Q.; Mavromoustakos, T.; Maia, H.; Ganter, R.; Moore, G. J. J. Med. Chem. 1995, 38, 4660) using 1-D NOE spectroscopy coupled with the present study of the same type of lead antagonist Sarilesin revealed that the Tyr4-Ile5-His6 bend, a conformational property found in Angiotensin II is not present in type I antagonists. The obtained results provide an important conformational difference between Angiotensin II agonists and type I antagonists. It appears that our synthetic attempt to further support our proposed model was successful and points out that the charge relay system and aromatic ring cluster are essential stereoelectronic features for Angiotensin II to exert its biological activity.     

BUCHBESPRECHUNGEN

S tebbins , L. (Hrsg.): Evolutionsprozesse. Bd. 2: Grundbegriffe der modernen Biologic Aus dem Amerikanischen von J utta Querner.
Systematische Zoologie. Stämme des Tierreichs. Begründet von A. R emane , V. S torch und U. W elsch .
K ämpfe , L. (Hrsg.): Evolution und Stammesgeschichte der Organismen. Bearb. von D. B ernhardt , F. F ukarek , E. G unther , L. K ämpfe .
L arwood , G. P.; A bbott , M. B. (Eds.): Advances in Bryozoology. Proceedings of the 4th International Conference of the International Bryozoology Association, Woods Hole, 1977.
Verhandlungen der Deutschen Zoologischen Gesellschaft. 72. Jahresversammlung vom 4.-9. Juni 1979 in Regensburg. Im Auftrag der Gesellschaft herausgegeben von Professor Dr. W. Rathmayer, Konstanz. Mit Beiträgen von zahlreichen Fachspezialisten.
R iedl , R., unter Mitarbeit von R. KASPAR: Biologie der Erkenntnis. Die stammesge-schichtlichen Grundlagen der Vemunft.
R emane , A.; S torch , V.; W elsch , U.: Kurzes Lehrbuch der Zoologie. 3., völlig neu bearbeitete Aufl.
K uhn , O.: Handbook of Paleoichthyology. Vol. 5: Acanthodii. By R. DENISON. Stuttgart und New York: Gustav Fischer 1979.
S tephan , H.; B aron , G.; S chwerdtfeger , W. K.: The brain of the Common Marmoset (Callithrix jacchus). A stereotaxic adas. Berlin, Heidelberg, New York:     

Book Reviews

Wilkinson, R. E. (ed.) Plant-Environment Interactions, Second Edition.
Stacey, G.; Keen, N. T. (eds) : Plant-Microbe Interactions.
Shurtle, M. C.; C. W. Averre Ill : Diagnosing Plant Diseases Caused by Nematodes.
Tjamos, E. C., R. C. Rowe, J. B. Heale, D. R. Fravel (eds) : Advances in Verticillium: Research and Disease Management.
Frederiksen, R. A.; G. N. Odvody (eds) : Compedium of Sorghum Diseases.
Podila, G. K., D. D. Douds Jr. (eds) : Current Advances in Mycorrhizae Research.
Kronstad, J. W. (ed.) : Fungal Pathology.
Agrawal, A. A., S. Tuzun, E. Bent (eds) : Induced Plant Defenses against Pathogens and Herbivores. Biochemistry, Ecology, and Agriculture.
Bartels, G.; Backhaus, G. F. (Hrg.) : Die Pr̈ng von Panzen auf ihre Widerstandsfhigkeit gegen Schadorganismen in der Biologischen Bundesanstalt. Teil 2 Resistenzpr̈ng von Kulturpanzen im Acker- und Gartenbau gegen Pilze, Bakterien und Viren-Testing of crop cultivars for resistance to noxious organisms at the Federal Biological Research Centre. Part 2. Testing of resistance of field and horticultural crops to fungi, bacteria and viruses. Mitt. Biol. Bundesanstalt för Land- und Forstwirtschaft, Berlin-Dahlem, Heft 373.
Bacon, Ch. W., L. F. White Jr. (eds) : Microbial Endophytes.
Siddiqi, M. R. : Tylenchida. Parasites of Plants and Insects.
Khetan, S. K. : Microbial Pest Control.
Upadhyay, R. K., K. G. Mukerji, B. P. Chamola (eds) : Biocontrol Potential and its Exploitation in Sustainable Agriculture.     

Steroidal derived acids as inhibitors of human Cdc25A protein phosphatase

A group of steroidal derived acids were synthesized and found to be human Cdc25A inhibitors. Their potency ranged from 1.1 to > 100 microM; the best ones compare very favorably with that of the novel cyano-containing 5,6-seco-cholesteryl acid 1 (IC50=2.2microM) reported by us recently (Peng, H.; Zalkow, L. H.; Abraham, R. T.; Powis, G. J. Med. Chem. 1998, 41, 4677). Structure-activity relationships of these compounds revealed that a hydrophobic cholesteryl side chain and a free carboxyl group are crucial for activity. The distance between these two pharmacophores is also important for the potency of these compounds. Several of the compounds showed selective growth inhibition effects in the NCI in vitro cancer cell line panel.     

Identification of SQ609 as a lead compound from a library of dipiperidines

We recently reported that compounds created around a dipiperidine scaffold demonstrated activity against Mycobacterium tuberculosis (Mtb) (Bogatcheva, E.; Hanrahan, C.; Chen, P.; Gearhart, J.; Sacksteder, K.; Einck, L.; Nacy, C.; Protopopova, M. Bioorg. Med. Chem. Lett.2010, 20, 201). To optimize the dipiperidine compound series and to select a lead compound to advance into preclinical studies, we evaluated the structure-activity relationship (SAR) of our proprietary libraries. The (piperidin-4-ylmethyl)piperidine scaffold was an essential structural element required for antibacterial activity. Based on SAR, we synthesized a focused library of 313 new dipiperidines to delineate additional structural features responsible for antitubercular activity. Thirty new active compounds with MIC 10-20 μg/ml on Mtb were identified, but none was better than the original hits of this series, SQ609, SQ614, and SQ615. In Mtb-infected macrophages in vitro, SQ609 and SQ614 inhibited more than 90% of intracellular bacterial growth at 4 μg/ml; SQ615 was toxic to these cells. In mice infected with Mtb, weight loss was completely prevented by SQ609, but not SQ614, and SQ609 had a prolonged therapeutic effect, extended by 10-15 days, after cessation of therapy. Based on in vitro and in vivo antitubercular activity, SQ609 was identified as the best-in-class dipiperidine compound in the series.     

BUCHBESPRECHUNGEN

Book reviewed in this article:
Verhandlungen der Deutschen Zoologischen Gesellschaft. Proceedings of the German Zoological Society. 71. Jahresversammlung vom 15. - 20.
B eermann , W.; G ehring , W. J.; G urdon , J. B.; K afatos , F. C., R einert , J. (Eds.): Results and Problems in Cell Differentiation. A Series of Topical Volumes in Developmental Biology.
S impson , G. G.: Splendid isolation. The curious history of south american mammals. New Haven and London:
S chäfer , K. E. (Ed.): Topics in Environmental Physiology and Medicine. HOIXWICH, F.: The Influence of Ocular Light Perception on Metabolism in Man and in Animal.
P ohowsky , R. A.: The Boring Ctenostomate Bryozoa: Taxonomy and Paleobiology Based on Cavities in Calgareous Substrata.
F erguson , A.: Biochemical Systematica and Evolution. Glasgow, London: Blackie&Son Ltd 1979.
N agl , W.: Chromosomen. Organisation, Funktion und Evolution des Chromatins. "Pareys Studientexte" Nr. 23. 2., neubearb. u. erw. Aufl.
S chliephak g e , G.; K limt , K.: Thysanoptera, Fransenflügler. Tierwelt Deutschlands 66.     

BUCHBESPRECHUNGEN

Book reviewed in this article:
DUNCKER, H.-R.; FLEISCHER, G. (Eds.): Functional Morphology of Vertebrates.
JEFFERIES, R. P. S.: The Ancestry of the Vertebrates.
HECHT, M. K.; OSTROM, J. H.; VIOHL, G.; WELLENHOFER, P. (Eds.): T h e beginnings of birds.
NICKEL, R.; SCHUMMER, A.; SEIFERLE, E.: The Anatomy of the domestic animals.
RIEDL, R.: Begriff und Welt.
RINDERER, TH. E. (Ed.): Bee genetics and breeding.
CHINERY, M.: Insekten Mitteleuropas. Ein Taschenbuch fur Zoologen und Natur-freunde. 3. Aufl. Ubers. u. bearb. von IRMGARD und DIETER JUNG.
VERMEIJ, G. J.: Evolution and escalation.
BARTH, F. G. (Ed.): Verhandlungen der Deutschen Zoologischen     

BUCHBESPRECHUNGEN

D ickinson , W. J.; S ullivan , D.T.: Gene-Enzyme Systems in Drosophila.
K ampmann , H.: Der Waschbär.
B aron , ST.: Die achte Plage.
O hno , S., Animal cytogenetics. Vol. 4, 1.
The Early Life History of Fish. The Proceedings of an International Symposium Held at the Dunstaffnage Marine Research Laboratory of the Scottish Marine Biological Association at Oban, Scotland, from May 17-23, 1973.
H ays , H. R.: Forscher entdecken die Tierwelt. Aus dem Amerikanischen übers. von D. J ensen .
H eymer , A.: Verhaltensstudien an Prachtlibellen. Fortschr. d. Verhaltensforsch. 11. Berlin u. Hamburg: Paul Parey 1973.
S tern /T igerstedt : Ökologische Genetik. Stuttgart: Gustav Fischer Verlag 1974.
Verhandlungen der Deutschen Zoologischen Gesellschaft. Proceedings of the German Zoological Society. 67. Jahresversammlung vom 3.-8. 6. 1974 in Bochum. Mit Bei-tragen von zahlreichen namhaften Fachspezialisten. Im Auftrage der Gesellschaft her-ausgegeben von Prof. Dr. WERNER R athmeyer , Konstanz 1975. XII.
Mechanisms of Spatial Perception and Orientation as Related to Gravity.
A utrum , H.; J ung , R.; L oewenstein , W. R.; M ac K ay , D. M.; T euber , H. L.: Handbook of Sensory Physiology. 3, Part 3
H ayman , D. L.; M artin : Animal Cytogenetics. 4, 4.
S chmidt -N ielsen , K.: Physiologische Funktionen bei Tieren. Aus dem Amerikani-schen von Dr. R uth B artels . Stuttgart: Gustav Fischer 1975. VIII     

Expression of multiple Src family kinases in sea urchin eggs and their function in Ca release at fertilization

Egg activation at fertilization in deuterostomes requires a rise in intracellular Ca²⁺, which is released from the egg's endoplasmic reticulum. In sea urchins, a Src Family Kinase (SpSFK1) is necessary for the PLCγ-mediated signaling event that initiates this Ca²⁺ release (Giusti, A.F., O'Neill, F.J., Yamasu, K., Foltz, K.R. and Jaffe, L.A., 2003. Function of a sea urchin egg Src family kinase in initiating Ca2+ release at fertilization. Dev. Biol. 256, 367-378.). Annotation of the Strongylocentrotus purpuratus genome sequence led to the identification of additional, predicted SFKs (Bradham, C.A., Foltz, D.R., Beane, W.S., Amone, M.I., Rizzo, F., Coffman, J.A., Mushegian, A., Goel, M., Morales, J., Geneviere, A.M., Lapraz, F., Robertson, A.J., Kelkar, H., Loza-Coll, M., Townley, I.K., Raisch, M., Roux, M.M., Lepage, T., Gache, C., McClay, D.R., Manning, G., 2006. The sea urchin kinome: a first look. Dev. Biol. 300, 180-193.; Roux, M.M., Townley, I.K., Raisch, M., Reade, A., Bradham, C., Humphreys, G., Gunaratne, H.J., Killian, C.E., Moy, G., Su, Y.H., Ettensohn, C.A., Wilt, F., Vacquier, V.D., Burke, R.D., Wessel, G. and Foltz, K.R., 2006. A functional genomic and proteomic perspective of sea urchin calcium signaling and egg activation. Dev. Biol. 300, 416-433.). Here, we describe the cloning and characterization of these 4 additional SFKs and test their function during the initial Ca²⁺ release at fertilization using the dominant-interfering microinjection method coupled with Ca²⁺ recording. While two of the new SFKs (SpFrk and SpSFK3) are necessary for Ca²⁺ release, SpSFK5 appears dispensable for early egg to embryo transition events. Interestingly, SpSFK7 may be involved in preventing precocious release of Ca²⁺. Binding studies indicate that only SpSFK1 is capable of direct interaction with PLCγ. Immunolocalization studies suggest that one or more SpSFK and PLCγ are localized to the egg cortex and at the site of sperm-egg interaction. Collectively, these data indicate that more than one SFK is involved in the Ca²⁺ release pathway at fertilization.