Phenotypic plasticity and genetic control in colorectal cancer evolution.

Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity1. The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather 'plastic'. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour

The synthesis and electronic absorption spectra of 3-phenyl-3(4-pyrrolidino-2-substituted phenyl)-3H-naphtho[2,1-b]pyrans: further exploration of the ortho substituent effect

Introduction of a substituent into a sterically demanding 2-position of a 3-(4-pyrrolidinophenyl) ring of a 3,3-diaryl-3H-naphtho[2,1-b]pyran results in the generation of an additional short wavelength absorption band leading to organic photochromes that appear as dull shades of orange and red

Control of the fading properties of photochromic 3,3-diaryl-3H-naphtho[2,1-b] pryans

The synthesis and spectroscopic properties of some novel photochromic 3H-naphtho[2,1-b]pyrans are reported. Varying the size of an ortho-substituent on one of the geminal aryl rings allows the rate of fade of the photogenerated color to be controlled

Vibrational assignment of the spectral data and thermodynamic properties of 2-chloro-4-fluorobenzophenone using DFT quantum chemical calculations

The FT-Raman (3500–100 cm−1) and FT-IR (4000–450 cm−1) spectra of 2-chloro-4-fluorobenzophenone were recorded in the solid phase. Density functional theory calculations with B3LYP/6-31G (d, p) basis set was used to determine the ground state molecular geometries (bond lengths and bond angles), harmonic vibrational frequencies, infrared intensities and Raman activities of this compound. Potential energy distributions (PEDs) and normal modes, for the spectral data computed at B3LYP/6-31G (d, p) level, have also been obtained from force-field calculations. The wavenumbers found after scaling of the force field showed very good agreement with the experimentally determined values. A comparison of the theoretical spectra and experimental FT-IR and FT-Raman spectra of the title molecule has been made and full vibrational assignments of the observed spectra have been proposed. On the basis of vibrational analyses, the thermodynamic properties of title compound at different temperatures have been calculated

Structural studies of a novel heterocyclic phosphorane

Reaction of 2,2,6-trimethylthiochroman-3,4-dione with an excess of methylenetriphenylphosphorane yields the stabilised ylide (4) by way of an α-ketol rearrangement. X-Ray crystallography indicates that (4) exists as the (a-isomer and provides supporting evidence for an enolate structure

Carbenoid induced irreversible ring opening of naphthopyrans

Contrary to expectation rhodium carbenoids do not undergo cycloaddition to the 2H-pyran unit of the isomeric naphthopyrans 3 and 5. With 3, a naphtho[2,1-b]pyran-8-ylacetate, 4 is formed and a novel merocyanine dye 6 results from a cycloaddition across the C-5-C-6 double bond of the naphtho[1,2-b]pyran 5. Tethering the carbenoid to the naphtho[1,2-b]pyran system 5, as in 10, results in a similar mode of addition and affords the intensely coloured tetracycle 11

Synthesis of some thiochromeno 4,3-c - and 3,4-c -pyrazoles

Reaction of 3-hydroxymethylene- and 3-cyanomethylene-thiochroman-4-ones with various hydrazine derivatives affords 4H-thiochromeno[4,3-c]pyrazoles. The novel isomeric thiochromeno[3,4-c]pyrazoles result when 4-(dimethylaminomethylene)thiochroman-3-ones react with methyl- and phenyl-hydrazines. Acidic hydrolysis of 3-(dimethylhydrazonoethylidene)-2,2,6-trimethylthiochroman-4-one yields the 3-cyanomethylenethiochroman-4-one. Formation of 6-chloro-3-hydroxymethylenethiochroman-4-one is accompanied by a thiochroman-3-yl(oxothiochromen-3-yl)methane derivative produced through a rearrangement-carbocation interception sequence. A 3-isopropenylthiochromenone, obtained by the acid promoted rearrangement of a 3-hydroxymethylenethiochroman-4-one, undergoes Diels-Alder cycloadditions to provide a new route to thioxanthenones

Conjugate addition of a phosphorus ylide to 3-cyanochromone

Reaction of 3-cyanochromane with methylenetriphenylphosphorane yields the stabilised ylide (4) by way of a conjugate addition and subsequent ring opening. Variable temperature H-1 NMR spectroscopy indicates that this ylide undergoes rapid conformational interconversion at ambient temperature. X-ray crystallography established that (4) exists as the (E) isomer in the solid state

Conjugate additions of lithium dialkynylcuprates (RC C)(2)CuLi to activated chromones. Unexpected formation of the 6H-bis 1 benzopyrano 2,3-b : 3',4'-e pyridine system

Lithium dialkynylcuprates [(RCequivalent toC)(2)CuLi], 1a-d, are easily generated and undergo conjugate additions to activated chromones giving 2-alkynylchroman-4-ones 4a-d, 13, 15c,d and 5, however, 1,4-additions to 3 proceed anomalously to give the eneynonitriles 6a-b and the bisbenzopyranopyridine 7

Synthesis and photochromic properties of substituted 3H-naphtho [2,1-b] pyrans

The synthesis and spectroscopic properties of novel 3H-naphtho[2, 1-b]pyrans are described. Subtle variation of the colour of the photo-generated merocyanine dyes derived from these naphthopyrans can be accomplished by controlling the steric interactions between a terminal pyrrolidine donor group and a proximal substituent