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Introduction: Up to 30% of all human cancers are driven by the overactivation of RAS signaling. Son of Sevenless 1 (SOS1) is a central node in RAS signaling pathways and modulation of SOS1-mediated RAS activation represents a unique opportunity for treating RAS-addicted cancers. Several recent publications and patent documents have demonstrated the ability of small molecules to affect the activation of RAS by SOS1 and have shown their potential for the treatment of cancers driven by RAS mutants.Areas covered: Documents focusing on both small-molecule inhibitors and activators of the SOS1:RAS interaction and their potential use as cancer therapeutics are covered. A total of 10 documents from 4 applicants are evaluated with discussion focusing on structural modifications of these compounds as well as relevant preclinical data.Expert opinion: The last decade has seen a significant increase in research and disclosures in the development of small-molecule SOS1 inhibitors. Considering the promising data that have been disclosed, interest in this area of research will likely remain strong for the foreseeable future. With the first SOS1 inhibitor currently in phase I clinical trials, the outcome of these trials will likely influence future development of SOS1 inhibitors for treatment of RAS-driven cancers.

In order to analyze and visualize big data with a large variety of data, we need an agile and flexible software system. Following the traditional standard programming paradigm, such a system cannot easily be built. This article introduces a programming approach that combines generic programming, pattern-oriented programming, and agent-oriented programming. Reflection techniques that allow components and patterns to change their behavior depending on the data context are also presented. The main motivation of aspect-oriented programming, the separation of concerns, is also discussed. This approach provides guidelines for building flexible, extensible, and maintainable software systems. However, a paradigm shift in programming is required, which is also presented in this article.

The generation of pyridynes from diyne nitriles is reported. These cyano-containing precursors are analogues of the triyne substrates typically used for the hexadehydro-Diels–Alder (HDDA) cycloisom...

Testing software is a process of program execution with the intent to find errors. For this purpose, various testing techniques have been used over time. Testing software is an intensive field of research in which much development work has been done. This field will become increasingly important in the future. There are many techniques for software testing. This chapter gives an overview of the entire range of software testing with suggestions for their implementation. One focus is on testing in an agile development process why the different types of software tests are important, and their cycle and methodology are described. In addition, different levels, types, and a comparative study on different types of tests are presented. The chapter also includes suggestions for performing the various tests and an effective approach to testing a software system.

The guanine nucleotide exchange factor (GEF) protein SOS1 activates RAS by promoting its conversion from the GDP-bound RAS(OFF) state to the GTP-bound RAS(ON) state. SOS1 catalyzes or accelerates this nucleotide exchange reaction in response to upstream signals conveyed by a range of growth factor receptors. It acts by promoting the release of tightly bound GDP and thereby facilitating the binding of GTP, which is present at higher intracellular concentrations than GDP, to generate RAS(ON). SOS1 itself is activated by RAS through the binding of RAS(ON) to an allosteric site on the SOS1 protein, which leads to a positive feedback loop between SOS1 and RAS that increases the amplitude and duration of RAS signaling. As a result, there is considerable potential for amplification of RAS signals by SOS1. For this reason, and because SOS1 is a convergent node downstream of RTK signaling, SOS1 represents an attractive therapeutic target in RAS driven cancers. We have developed a collection of novel, proprietary small molecule inhibitors of SOS1. Here we describe the preclinical profile of a potent, selective, and orally bioavailable in vivo tool compound, RM-023, which disrupts the critical interaction between KRAS and SOS1. By preventing formation of the KRAS-SOS1 complex, these inhibitors block reloading of KRAS with GTP, and thereby inhibit RAS pathway signaling and RAS-driven cancer cell growth in vitro. Oral administration of RM-023 produced a dose-dependent suppression of tumor RAS pathway activation in vivo and inhibited tumor growth in preclinical xenograft models of diverse RAS-addicted cancers at well-tolerated doses. Enhanced anti-tumor activity in RAS-addicted cancer models was observed when RM-023 was administered in combination with other RAS pathway inhibitors. We believe SOS1 inhibition represents an attractive companion for combination with RAS-directed inhibitors and may have unique utility in select RAS-addicted tumor types. Citation Format: Andreas Buckl, Elsa Quintana, Grace J. Lee, Nataliya Shifrin, Mengqi Zhong, Lindsay S. Garrenton, David C. Montgomery, Carlos Stahlhut, Frances Zhao, Dan M. Whalen, Severin K. Thompson, Arlyn Tambo-ong, Micah Gliedt, John E. Knox, James J. Cregg, Naing Aay, Jong Choi, Bao Nguyen, Atti Tripathi, Ruiping Zhao, Mae Saldajeno-Concar, Abby Marquez, Daphne Hsieh, Laura L. McDowell, Elena S. Koltun, Alun Bermingham, David Wildes, Mallika Singh, Zhengping Wang, Richard Hansen, Jan A. Smith, Adrian L. Gill. Discovery of a potent, selective, and orally bioavailable SOS1 inhibitor, RMC-023, an in vivo tool compound that blocks RAS activation via disruption of the RAS-SOS1 interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1273.

Unfavorable thermodynamics often render furans reluctant to engage in high-yielding Diels-Alder (DA) cycloaddition reactions. Here, we report the highly efficient conversion of the biosourced reactants itaconic anhydride (IA) and furfuryl alcohol (FA) to a single DA adduct. The free energy advantages provided by anhydride ring opening and crystal lattice energy of the product overcome the loss of aromaticity of the furanoid diene. Detailed (1)H NMR studies provided valuable insights about relevant kinetic and thermodynamic features.

In the classic Diels-Alder [4 + 2] cycloaddition reaction, the overall degree of unsaturation (or oxidation state) of the 4π (diene) and 2π (dienophile) pairs of reactants dictates the oxidation state of the newly formed six-membered carbocycle. For example, in the classic Diels-Alder reaction, butadiene and ethylene combine to produce cyclohexene. More recent developments include variants in which the number of hydrogen atoms in the reactant pair and in the resulting product is reduced by, for example, four in the tetradehydro-Diels-Alder (TDDA) and by six in the hexadehydro-Diels-Alder (HDDA) reactions. Any oxidation state higher than tetradehydro (that is, lacking more than four hydrogens) leads to the production of a reactive intermediate that is more highly oxidized than benzene. This increases the power of the overall process substantially, because trapping of the reactive intermediate can be used to increase the structural complexity of the final product in a controllable and versatile manner. Here we report an unprecedented overall 4π + 2π cycloaddition reaction that generates a different, highly reactive intermediate known as an α,3-dehydrotoluene. This species is in the same oxidation state as a benzyne. Like benzynes, α,3-dehydrotoluenes can be captured by various trapping agents to produce structurally diverse products that are complementary to those arising from the HDDA process. We call this new cycloisomerization process a pentadehydro-Diels-Alder (PDDA) reaction-a nomenclature chosen for chemical taxonomic reasons rather than mechanistic ones. In addition to alkynes, nitriles (RC≡N), although non-participants in aza-HDDA reactions, readily function as the 2π component in PDDA cyclizations to produce, via trapping of the α,3-(5-aza)dehydrotoluene intermediates, pyridine-containing products.

An innovative combination of chemical synthesis, theory and spectroscopy could simplify determination of the structures of naturally occurring, biologically active molecules, which are often leads for drug discovery. See Letter p.436 Molecules are often drawn as though they are static chemical structures, but of course in reality they adopt a number of different conformations. The structures of flexible compounds are especially difficult to pin down by conventional means as they can appear as a mixture of conformational isomers. Baulamycins, polyketide antibiotics with long, flexible carbon chains, are one such example and, although they have been the target of synthetic efforts, the true structure of the natural product is unclear. Here, Varinder Aggarwal and colleagues elucidate the structure of the baulamycins by a method based on the correlation of experimental and computed nuclear magnetic resonance data and an iterative synthetic strategy to the target compounds. This approach allowed the unambiguous and correct assignment of the stereocentres and the structure of these natural products and could be applied to other such complex, flexible systems.

Neoplastic diseases are among the leading health concerns in medicine. As such, epidemiological studies considering canine tumours are benefi cial in understanding the patterns of tumour occurrence. The aim of this study was to analyze data on the occurrence of canine tumours in Croatia. From 1 January 2006 to 31 December 2009, a total of 1568 tumours were diagnosed after routine biopsy submission or necropsy. The WHO classifi cation was used for designating tumour type. Most tumours (59.1%) were malignant, 35.4% were benign, while the remainder (5.29%) were treated as not specifi ed. Tumours originated from the skin and subcutis (45.73%), mammary gland (21.75%) and genital system (7.97%). The most common specifi c tumour types diagnosed were mammary tubulopapillary carcinoma (7.14%), mast cell tumour (4.91%) and fi brosarcoma (4.91%). Differences in tumour occurrence in dog populations from inland and coastal areas were negligible in all but mammary tumours (20.54% in inland ; 28.63% in coastal areas) and mammary tubulopapillary carcinoma (6.37% in inland ; 11.54% in coastal areas). Using data from the Croatian national registry of vaccinated dogs, the crude incidence of tumours was calculated only for the Zagreb area. Expressed as the number of tumours per 100, 000 dogs per year, the incidence was 1504 for all tumours, 532 for benign and 790 for malignant tumours. The overall frequencies of dominant tumour types and the crude incidence of canine tumours in the Zagreb area are comparable to other investigations.

The molecular forms of LiF, LiFHF and Na2SiF6 have been stabilized using trinuclear metallamacrocyclic complexes of (cymene)Ru-II, (Cp*)Rh-III and (Cp*)Ir-III as specific receptors. The host-guest complexes were characterized by NMR spectroscopy and single crystal X-ray diffraction. Based on these results, a highly selective chemosensor for fluoride anions has been developed.

The trinuclear arene-ruthenium cluster cation, [Ru3H3(O)(C10H14)2(C14H16O4)](+), has been synthesized and crystallized as the tetrafluoroborate (BF4-) salt. The cations form, along the b axis, infinite one-dimensional chains through pi-stacking interactions.

The reaction of [(arene)RuCl2](2) (arene = cymene, 1,3,5-C6H3Me3) and [Cp*RhCl2](2) half-sandwich complexes with tridentate heterocyclic ligands in the presence of base has been investigated. In all cases, the chloro-ligands were substituted to give metallacyclic products with ring sizes between 4 and 18 atoms. The cyclization occurs in a highly diastereoselective fashion with chiral recognition between the different metal fragments. The complexes were comprehensively characterized by elemental analysis, NMR spectroscopy, and single crystal X-ray crystallography. For 2-hydroxy-nicotinic acid and 2-amino-nicotinic acid, dinuclear structures were obtained (1517) whereas for 2,3-dihydroxyquinoline, 2,3-dihydroxyquinoxaline, and 6-methyl-2,3-phenazinediol, trimeric assemblies were found (19-22), and for 4-imidazolecarboxylic acid, a tetrameric assembly (18) was found.

Chloro-(h6-arene) complexes of Ru(II) with N-sulfonyl-1,2-ethylenediamine ligands that have one or two styrene side chains were synthesized and characterized. The chloro ligand was substituted with a diphenylphosphinato ligand and the resulting organometallic complexes are transition state analogs for the Ru-catalyzed transfer hydrogenation of benzophenone. Following the protocol of mol. imprinting, these complexes were copolymd. with ethylene glycol dimethacrylate (EGDMA) in the presence of a porogen. The polymers were ground and sieved, and the phosphinato ligand was substituted with a chloro ligand, thus generating a shape-selective cavity in close proximity to the catalytically active metal center. When tested for their ability to catalyze the redn. of benzophenone, the imprinted polymers showed a significantly higher activity (up to a factor of seven) than control polymers without cavities. Out of a mixt. of seven different arom. and aliph. ketones, benzophenone was preferentially reduced when the imprinted polymer was used. Also, the specificity of the catalyst for diaryl ketones was confirmed in a reaction with a bifunctional substrate, 4-acetyl-benzophenone; the diaryl ketone was reduced faster with the imprinted catalyst than the acetyl group. The opposite regioselectivity was obsd. with the control polymer. Both the activity and the selectivity of the imprinted catalysts are dependent on how the Ru complexes are attached to the polymer backbone. A double connection proved to give superior results.

The prepn. of redox-responsive metallomacrocyclic ionophore I, which is easily obtained by the reaction of [(cymene)RuCl2]2 with 3-hydroxy-2-pyridone in the presence of Cs2CO3 or K2CO3, is described. The binding const. of the LiCl and the NaCl with I is comparable to that of high-affinity ionophores such as cryptands, and has a nearly perfect selectivity for Na+ over K+. Preliminary results indicate that structurally related metallacrown ethers having different arene ligands (e.g., C6Me6, C3H3Et3) instead of cymene can be assembled using the strategy described here. Since the selectivity of the ionophore is detd. by these ligands, redox-responsive receptors with designed specificities and solubilities can be envisioned. The crystal structure of I and its complex with Li and Na is detd

Durch Reaktion von [(OC)2MCl]2 (M = Rh, Ir) oder [(cod)RhCl]2 mit den Anionen von N‐Aryl‐ oder N‐Alkyl‐substituierten 3‐Hydroxy‐2‐methyl‐4‐pyridonen (O–O′) wurden Komplexe der allgemeinen Formel [L2M(O–O′)] (1–7) erhalten. Verbindungen dieses Typs konnten auch durch Umsetzung von [(OC)2Rh(acac)] (acac = Acetylacetonat) mit den entsprechenden neutralen Liganden synthetisiert werden. Der N‐Phenyl‐Komplex [(OC)2Rh(C12H10NO2)] (2) reagiert mit Cycloocten unter Substitution eines Carbonyl‐Liganden zu [(OC)(C8H14) · Rh(C12H10NO2)] (8). Palladium‐Komplexe der Formel [(R3P)Pd(O–O′)Cl] (R = Et, Bu), [(C6H4CH2NMe2)Pd(O–O′)] und [(Et3P)2Pd(O–O′)]BF4 (9–12) wurden ausgehend von [(R3P)PdCl2]2, [(C6H4CH2NMe2)PdCl]2 oder [(Et3P)PdCl2] dargestellt. Die Strukturen der N‐Methyl‐Verbindungen [(OC)2Rh(C7H8NO2)] (1) und [(Ph3P)Pd(C7H8NO2)Cl] (9) wurden durch Einkristall‐Röntgenstrukturanalysen bestimmt.

The reaction of [ReBr3(CO)(3)][NEt4](2) with 3-hydroxy-1,2,3-benzotriazine-4 (3 H) -one in the presence of base gave the ionic rhenium complex [ReBr(C7H4N3O2)(CO)(3)][NEt4] (2) which was crystallographically characterized. A neutral metallamacrocycle 3 was obtained upon abstraction of [NEt4]Br from complex 2. This complex cocrystallizes with an unusual C-3-symmetric [Ag(eta(1)-benzene)(3)(OH2)][BF4] complex as evidenced by single-crystal X-ray diffraction. (C) Wiley-VCH Verlag GmbH Co.

Indicator displacement assays based on the organometallic complex [Cp*RhCl2]2 and the dye gallocyanine have been used to sense aminosugars and aminoglycosides in buffered aqueous solution by UV-Vis spectroscopy. The data of three assays at pH 7.0, 8.0 and 9.0 were sufficient to distinguish the aminosugars galactosamine, glucosamine, mannosamine and the aminoglycosides kanamycin A, kanamycin B, amikacin, apramycin, paromomycin and streptomycin. Furthermore, the assays were used to characterize mixtures of aminoglycosides and obtain quantitative information about the respective analytes.

The homo- and heterobimetallic complexes [Cp*Ru(m-Cl)3-ML] [LM = (C6H6)Ru, (cymene)Ru, (1,3,5-C6H3iPr3)Ru, Cp*Rh, Cp*Ir] were prepd. by reaction of [Cp*Ru(m-OMe)]2 with Me3SiCl and subsequent addn. of [LMCl2]2. The complexes [Cp*Ru(m-Cl)3Ru(cymene)] and [Cp*Ru(m-Cl)3-IrCp*] were characterized by single-crystal X-ray analyses. In crossover expts. with [Cp*Rh(m-Cl)3RuCl(PPh3)2] and [Cp*Ru(m-Cl)3Ru(1,3,5-C6H3iPr3)] in CD2Cl2, a dynamic equil. with the complexes [Cp*Rh(m-Cl)3RuCp*] and [(1,3,5-C6H3iPr3)Ru(m-Cl)3RuCl(PPh3) 2] was rapidly established, demonstrating the kinetic lability of the triple chloro bridge. Upon reaction of [Cp*Rh(m-Cl)3RuCp*] with benzene, the ionic complex [Cp*Ru(C6H6)][Cp*RhCl3] was formed, which was characterized by X-ray crystallog.

An organometallic transition state analog for the asym. redn. of acetophenone with a Cp*Rh complex was synthesized and structurally characterized - rac-[(C5Me5)Rh[OP(O)MePh](R,R-4-CH2:CHC6H4SO2NC6H10NH2)] (3). This complex has a chiral N,N'-chelate ligand with a styrene side chain to allow its incorporation into org. polymers. The remaining coordination site is occupied by a methylphenylphosphinato ligand. This ligand acts as a pseudo substrate which mimics acetophenone. The conformation and configuration of 3 in the crystal are in excellent agreement with the postulated transition structure. Following the protocol of mol. imprinting, complex 3 was co-polymd. with ethylene glycol dimethacrylate in the presence of a porogen. The resulting polymer P3 was ground and sieved and the phosphinato ligand was substituted with a chloro ligand to generate a shape-selective cavity in proximity to the catalytically active metal center. When tested for its ability to catalyze the redn. of acetophenone and related substrates the imprinted polymer P3 showed a significantly higher activity than a control polymer P2 without a cavity. Excellent enantioselectivities (up to 95% ee) were obtained, with the catalyst P3 being more selective than the resp. control catalyst P2 (Dee = 2-9%). Competition expts. with acetophenone and a 2nd co-substrate revealed that the cavity generated with the phosphinato ligand is specific for acetophenone.

The reaction of [(Et3P)PdCl2](2) with 2,3-dihydroxypyridine, 5-chloro-2,3,-dihydroxypyridine, or 2-hydroxynicotinic acid in the presence of base gives neutral, metallomacrocyclic compounds in which the heterocycles act as dianionic, bridging ligands. The macrocycles contain four or ten palladium atoms as evidenced by single crystal X-ray analyses.

A 33-residue de novo designed peptide ligase is reported which catalyzes the template-directed condensation of suitably activated short peptides with catalytic efficiencies in excess of 105 ([kcat/Km]/kuncat). The ligase peptide, derived from natural and designed a-helical coiled-coil proteins, presents a surface for substrate assembly via formation of a hydrophobic core at the peptide interface. Charged residues flanking the core provide addnl. binding specificity through electrostatic complementarity. Addn. of the template to an equimolar fragment soln. results in up to 4100-fold increases in initial reaction rates. Dramatic decreases in efficiency upon mutation of charged residues or increase in ionic strength establishes the importance of electrostatic recognition to ligase efficiency. Although most of the increase in reaction efficiency is due to entropic gain from binding of substrates in close proximity, mechanistic studies with altered substrates demonstrate that the system is highly sensitive to precise ordering at the point of ligation. Taken together these results represent the first example of a peptide catalyst with designed substrate binding sites which can significantly accelerate a bimol. reaction and support the general viability of a-helical protein assemblies in artificial enzyme design.

Die Hydrido‐Komplexe RuHCl(CO)(PPh3)3, RuH2(PPh3)4 und IrH3(PPh3)3 reagieren mit N‐Acyl‐α‐Amino‐carbonsäuren unter Bildung der Carboxylat‐Komplexe RuCl(O2CCHRNHCOR′)(CO)(PPh3)2 (1–3), RuH(O2CCHRNHCOR′)(PPh3)3 (4–6) und IrH2(O2CCH2NHCOPh)(PPh3)3 (7). Die Struktur von RuCl(O2CCH2NHCOPh)(CO)(PPh3)2 (1) wurde röntgenographisch bestimmt. Phosphan‐Komplexe der Formel MBr(O2CCH2NHCOR)(CO)2(PPh3)2 (M = Mo, W) (8–12) und Mo(O2CCHRNHCOR′)2(CO)2(PPh3)2 (13–17) entstehen bei der Umsetzung von MBr2(CO)2(PPh3)2 mit einem bzw. zwei Äquivalenten N‐Acyl‐α‐Aminocarboxylat‐Anionen.

Three immobilized Cu(II) complexes were generated by the following: (a) homopolymerization of the N,N',N '' chelate ligand tris[2-(1-vinylimidazolyl)]phosphine (1) and subsequent metalation with CuCl2; (b) copolymerization of 1 with ethyleneglycol dimethacrylate (EGDMA) und subsequent metalation with CuCl2; or (c) molecular imprinting with the organometallic Mo-complex (Mo(eta(3)-C4H7)(CO)(2)(1)](TsO) (5) and EGDMA and subsequent replacement of Mo(II) by Cu(II). All three polymeric Cu complexes were found to efficiently promote the hydrolysis of activated phosphoesters with the relative activity being dependent on the nature of the polymer and the substrate.

Metal Complexes of Biologically Important Ligands, LXX[1].- Synthesis, Stereochemistry and Reactions of Ruthenium(II) and Osmium(II) Complexes with -Amino Carboxylates. The reactions of MHCl(CO)(PPh3)3 with salts of -amino acids give the hydrido-N,O-chelate complexes MH(CO)(NH2CHR-COO)(PPh3)2 (1a-g;) M = Ru, Os). Complexes 1a-c can alternatively be prepared by oxidative addition of the appropriate -amino acid to Ru(CO)3(PPh3)2. The crystal structure of 1b has been determined by an X-ray structural analysis. The leucinato compound 1c is an effective catalyst for the decomposition of formic acid. In contrast, reactions of RuHCl-(CO)(PPh3)3 with -amino acids afford the chloro-N,O-che-late complexes RuCl(CO)(NH2CHRCOO)(PPh3)2 2a-h. The decomposition reactions of 2c, 2g and2h have been investigated.

The trinuclear Ru complexes [RuCl2(PAd2Bu)]3 (1) and [RuCl2(PtBu2Cy)]3 (2) were obtained by reaction of [(p-cymene)RuCl2]2 with 2 equiv of the resp. sterically demanding phosphine. Crystallog. analyses of 1 and 2 show that the three metal fragments are connected by strong Ru-Ru bonds and bridging chloro ligands. The chem. and thermal stability of the complexes were explored.

The reaction of [RuCl3(AsPh3)(2)(MeOH)] with the dimeric complexes [(cod)RhCl](2), [(ppy)RhCl](2) (ppy = cyclometalated 2-phenylpyridine), [(cymene)RuCl2](2) and [CP*MCl2](2) (M = Rh, Ir) has been investigated. The structure of the resulting products was shown to depend on the reaction partner. Whereas for the rhodium complexes [(cod)RhCl](2) and [(ppy)RhCl](2), heterobimetallic compounds with two halogeno-bridges were found, the reactions with the halfsandwich complexes [(cymene)RuCl2](2) and [CP*MCl2](2) gave triply bridged products with concomitant formation of mononuclear [(pi-ligand)MCl2(AsPh3)] side products. The new complexes were all characterized by single crystal X-ray analysis. (C) 2004 Elsevier B.V. All rights reserved.