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Indoles and Biindoles: Synthesis of Powerful Tools for Pharmaceutical and Materials Sciences
Get PDFPart 1: synthesis of indoles as potential bioactive compounds
Indole and related derivatives play a strong relevant role in heterocyclic chemistry. They are diffused in a
huge array of different natural products[1], many of them with intriguing biological activity.[2] Other
applications spread uncountable fields: material science, fragrances, agrochemicals, pigments and dyes and
many more.[3] It’s not surprising then that many efforts are made by organic chemists to find not only
synthetic methods to achieve indole fragments but also new functionalization protocols to afford with ease
complex targets.
Recently, Penoni group afforded a novel regioselective indole synthesis via annulation of variously
substituted nitrosoarenes and alkynes[4,5] (Figure 1). Main feature of this reaction is possibility to directly
prepare N-hydroxyindoles derivatives, when 4-nitronitrosobenzene is employed as reaction partner. High
efficiency on nitrosoarene-alkyne cycloaddition was noticed by trapping the formed unstable N-OH indole
product by methylation or interception with other electrophiles. Concerning other alkyne reactions with
other substituted nitrosobenzenes, indoles were detected as products; this feature was exploited to prepare
marine alkaloids meridianins and some modified aminoacids[6] (Figure 1). Reaction is supposed to pass
through a radical mechanism[7]
.
Figure 1: annulation reaction between alkynes and nitrosoarenes
3-Acylindoles(e.g. pravadoline, SCB01A, BPR0L075) are known to be bioactive compounds and recent studies
highlighted their interesting properties[8] and various synthetic approaches[9]. However, not many
indolization protocols are known to afford directly 3-acylindoles starting from easily available reactants.
Research topic was therefore focused on applying and optimizing nitrosoarene-alkyne one pot annulation
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approach for the preparation of highly functionalizable compounds and/or biologically active products having
the 3-aroylindole fragment (Figure 2). Noticeably, after careful reaction optimization, unprotected Nhydroxy-3-aroylindoles were regioselectively detected as main products in most cases and recovered as
perfectly stable solid after precipitation with no need of protecting groups[10–12]
. Internal alkynes gave poor
reactivity.
Figure 2: annulation reaction between alkynones and nitrosoarenes.
Interestingly, reaction between 4-nitronitrosobenzene and 3-bromo-1-phenylprop-2-yn-1-one gave
regioselectively a 2-brominated indole compound. It is set as an objective for the near future a wide substrate
scope for synthesis of different 2-brominated indoles (Figure 3). Studies of reactivity of the latter compounds
towards classical cross coupling reactions is expected as well (Figure 3).
Figure 3: synthesis of a N-hydroxy-3-aroyl-2-bromo-indole (left); reactivity of the latter to classic cross
coupling reactions (right).
Part 2: synthesis of new organic semiconductors based on 2,2’- and 3,3’- biindole backbone
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Inherently chiral materials based on 2,2’-biindole are characterized by an atropoisomeric backbone of two
2,2’ interconnected indole rings bearing 3,3’ substituents usually constituted by 2,2’-bitiophene units(Ind2T4,
Figure 4). Those substituents play the double role of hindering rotation around the interannular bond and
endowing system with specific properties. Main application of inherently chiral 2,2’-biindoles is as starting
materials to obtain enantiopure oligomeric selectors in chiral electrochemistry[13]
. Monomer oligomerization
is usually performed in electrochemical cell by many repeating anodic voltametric cycles to afford an
oligomeric coating directly on working electrode. Our interest in the chemistry of indoles led us to explore
the opportunity to get some analogous structure by structural modification of 3,3’-substituents. Introduction
of a π spacer (Ind2Ph2T4, Ind2T6, Figure 4) was performed to study its influence on chiral properties of resulting
oligomers, whilst introduction of a benzochalchogenodiazole subunit allows to achieve a donor-acceptor
moiety with interesting optical properties (Ind2BTD2T4, Ind2BSeD2T4, Figure 4).
Figure 4: enantiomers of Ind2T4 (left); target 2,2’-biindoles (right). R = alkyl.
Key core for synthesis of these compounds is a Larock-type 5-endo-dig double indole ring closure starting
from compound 1 (Scheme 1), as published by Abbiati in 2006[14]. This protocol shows good versatility as by
variation of aryl- or heteroaryl halide reaction partner is possible to prepare different 3,3’-diaryl/heteroaryl
2,2’-biindoles although in good to mediocre yield. Only racemate compounds are afforded due to lack of any
chiral catalyst. Subsequent nitrogen alkylation step is fundamental to ensure good solubility for processing.
Scheme 1: synthesis of 2,2’-biindoles starting from 1 and an aryl/heteroaryl halide.
4
All new compounds have been deeply characterized either monomeric or oligomeric. Separation of Ind2Ph2T4,
Ind2T6 in their two enantiomers was performed through semipreparative chiral HPLC, as up to now synthetic
method allows only to afford targets as racemate mixtures. After electrodeposition, Ind2Ph2T4 and Ind2T6
enantiopure oligomeric films showed great enantioselectivity towards both enantiomers of a chiral
ferrocenylamine (Figure 5).
Figure 5: cyclic voltammetry graphs showing different oxidation peaks for enantiopure oligo N-Pr-Ind2Ph2T4
(left) and N-Pr-Ind2T6 (right) towards two enantiomers of a chiral ferrocenylamine (bottom).
Concerning Ind2BTD2T4 and Ind2BSeD2T4, full characterization of monomers and electroactive films has been
carried out. Enantiorecognition tests are planned for next future.
Since Larock-type ring closure reaction has been proved very useful although mediocre yielding, a new and
more performant synthetic plan to afford Ind2T4 has been optimized (Scheme 2). Key step is high yield SuzukiMiyaura cross coupling reaction starting from compound 5. Future developments concern on use of different
boronic pinacol esters to afford Ind2Ph2T4, Ind2T6, Ind2BTD2T4 and Ind2BSeD2T4 in better yields as well.
5
Scheme 2: synthesis of Ind2T4 passing through a Suzuki cross coupling step.
Structural analogue 2,2’-diheteroaryl-3,3’-biindole 3,3’-Ind2T4 (Figure 6) was synthetized as well with the aim
to investigate its ability as chiral selectors. Unfortunately, when trying to separate them with chiral HPLC,
enantiomers peaks coalescence was noticed even at room temperature, suggesting configurational
instability.
Figure 6: synthesis of 3,3’-Ind2T4 (up); chiral HPLC profiles at different temperatures (bottom).
Computational studies indicated possibility to achieve configurational stability for 3,3’-biindoles by nitrogen
alkylation with very bulky tertbutyl group. Experiments in this direction are currently ongoing.
References:
[1] R. J. Sundberg, The Chemistry of Indoles, New York, 1970.
[2] V. Sharma, P. Kumar, D. Pathak, J. Heterocycl. Chem. 2010, 47, 491–502.
[3] T. C. Barden, Peptides 2011, 26, 31–46.
[4] A. Penoni, K. M. Nicholas, Chem. Commun. 2002, 2, 484–485.
[5] A. Penoni, J. Volkmann, K. M. Nicholas, Org. Lett. 2002, 4, 699–701.
[6] F. Tibiletti, M. Simonetti, K. M. Nicholas, G. Palmisano, M. Parravicini, F. Imbesi, S. Tollari, A. Penoni,
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Tetrahedron 2010, 66, 1280–1288.
[7] A. Penoni, G. Palmisano, Y. Zhao, K. N. Houk, J. Volkman, K. M. Nicholas, J. Am. Chem. Soc. 2009,
131, 653–661.
[8] D. G. Zhao, J. Chen, Y. R. Du, Y. Y. Ma, Y. X. Chen, K. Gao, B. R. Hu, J. Med. Chem. 2013, 56, 1467–
1477.
[9] S. J. Yao, Z. H. Ren, Z. H. Guan, Tetrahedron Lett. 2016, 57, 3892–3901.
[10] G. Ieronimo, G. Palmisano, A. Maspero, A. Marzorati, L. Scapinello, N. Masciocchi, G. Cravotto, A.
Barge, M. Simonetti, K. L. Ameta, et al., Org. Biomol. Chem. 2018, 16, 6853–6859.
[11] L. Scapinello, A. Maspero, S. Tollari, G. Palmisano, K. M. Nicholas, A. Penoni, J. Vis. Exp. 2020, 155, 1–
12.
[12] L. Scapinello, F. Vavassori, G. Ieronimo, K. L. Ameta, G. Cravotto, M. Simonetti, S. Tollari, G.
Palmisano, A. Maspero, K. M. Nicholas, et al., Manuscript in Preparation, 2020.
[13] S. Arnaboldi, T. Benincori, A. Penoni, L. Vaghi, R. Cirilli, S. Abbate, G. Longhi, G. Mazzeo, S. Grecchi,
M. Panigati, et al., Chem. Sci. 2019, 10, 2708–2717.
[14] G. Abbiati, A. Arcadi, E. Beccalli, G. Bianchi, F. Marinelli, E. Rossi, Tetrahedron 2006, 62, 3033–303
On the interaction between a fixed bed of solid material and the confining column wall: the Janssen approach
No full textClinico-pathological and biological characterization of a cohort of 140 patients affected by relapsed/refractory Diffuse Large B Cell Lymphoma: looking for prognostic factors.
Get PDFDiffuse Large B Cell Lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although most patients respond efficaciously to the first line therapy, about 30-40% are primary refractory or present relapse after an initial response, constituting a group with poor prognosis. Many efforts have been made to find prognostic factors, able to identify high-risk patients; however, the currently available scores are often inadequate to this purpose.
In this study we compared the clinical and biological features of a cohort of relapsed/refractory patients (R/R, n = 140), with those a cohort of patients not affected by relapse after at least 5 years of follow-up (controls, n = 45). We divided the R/R patients according to the time of relapse in three subgroups – refractory (characterized by persistence of disease or recurrence within 9 months from diagnosis, n = 72), early relapsed (with recurrence of disease within 10 and 24 months, n = 35) and late relapsed (with recurrence of disease beyond 24 months from diagnosis, n = 33). We also performed gene expression profiling (GEP) analysis on a subgroup of patients, aiming at recognizing differentially expressed genes; through this analysis, we identified the B1 subunit of NADH:Ubiquinone Oxidoreductase (NDUFB1) as a gene with enhanced expression in R/R patients. We further verified NDUFB1 expression and protein levels in DLBCL cell lines and performed ad hoc immunohistochemistry on patients’ samples.
Our results show that the R/R subgroups differentiate in terms of clinical and biological features, but also in terms of outcomes, with an inferior post-relapse overall survival (OS) for refractory patients. In the whole R/R cohort, we confirmed the prognostic value of the International Prognostic Index (IPI) and the Revised-IPI (R-IPI), even when calculated at relapse, and of well-known adverse factors (B-symptoms, advanced stage, lactate dehydrogenase (LDH) increase, bulky disease, extra-nodal involvement), but we also found a novel correlation between male sex and inferior progression-free survival (PFS) and OS, and between inflammatory indexes as neutrophils/lymphocytes (N/L) ratio, Systemic Immune-Inflammation Index (SII) and C-reactive protein value/albumin value (CAR) and outcome. As for immunohistochemistry data, high Ki67 values correlated with reduced OS, while NDUFB1 overexpression caused a PFS disadvantage. We detected a trend of more frequent altered expression of P53 in the R/R cohort, in which all patients with enhanced expression were refractory, while all cases with a “null” phenotype belonged to the late relapsed group. In the second line setting, 23% of patients underwent autologous stem cell transplant (ASCT); transplanted patients had a post-relapse OS significantly superior to patients who did not receive transplant.
Globally, we assessed the importance of the time of relapse for prognosis prediction, and identified some subgroup-specific features and variables impacting on outcome. These results, if validated in larger cohorts could contribute to the formulation of new prognostic scores, improving risk-stratification in DLBCL
Vibrational analysis of a flexible bicycle stem during indoor in-vivo cycling on a two rollers servohydraulic test bench
Get PDFIntroduction. Comfort is an important parameter correlated to bicycle usability and depends deeply on vibrations and human perception. The most of vibrations is generated by the interaction between road and wheels and sensed at hands and seat [1][2]. Different approaches were used to evaluate the in-vivo behaviour of different bycicle postures and components, including vibrational excitation applied to the wheels [2],[3]. The present work presents results obtained from a full scale roller bench test [3] on a flexible stem supposed to improve the riding comfort.
External vibrations were applied to both wheels using a two rollers servohydraulic test bench [3] with a random load function generator corresponding to road types defined by the ISO 8608: 2016.
Methods. A specific flexible stem (Shockstop produced by Redshift), designed to reduce accelerations transmitted to the hands by selectable elastomeric shock-absorbing inserts (SOFT, MEDIUM, HARD), was compared to a standard rigid stem (Deda zero 100 Alluminum). Three road profiles (A= Airport runways and super highways; B= Normal pavements; C= Unpaved and damaged roads, ISO 8608: 2016) were applied to the cyclist in two postures (Posture1-Hands on upper handlebar brakes, Posture2-Hands on handlebar drops).
Results. Table 1 reports the Comfort index and Transmission index percent variations respect to the RIGID stem (Red cells represent lower performance). As it can be seen, based on CI the Flexible stems seems to improve comfort in both postures and stem hardness with lower roas harshness, but gives not favourable results in Posture 1 with road C. The transmission index TI seems to give opposite results than the CI in Posture 1, whereas shows better agreement in posture 2.
Conclusions. The study shows the suitability of the roller test bench for the stationary analysis of comfort related component in bicycle. The significance of the two parameters CI and TI deserve comparison with a larger number of subjects and their subjective evaluation
Preparation and Reactivity of Germyl Complexes of Ruthenium and Osmium Stabilised by Cyclopentadienyl, Indenyl and Tris(pyrazolyl)borate Fragments
No full textHalf-sandwich trichlorogermyl complexes Ru(GeCl3)(h5 -C5H5)(PPh3)L (1) and Ru(GeCl3)(h5 -C9H7)(PPh3)L (2) [L ¼ P(OMe)3 (a), P(OEt)3 (b) and PPh(OEt)2 (c)] were prepared by allowing chloro compounds RuCl(h5 -C5H5)(PPh3)L and RuCl(h5 -C9H7)(PPh3)L to react with an excess of GeCl2dioxane. Depending on metal centre, nature of phosphite and experimental conditions, the reaction of trichlorogermyl complexes 7 and 10 with LiAlH4 or NaBH4 afforded trihydridogermyl M(GeH3)(Tp)(PPh3)L (8, 12) and triethoxygermyl derivatives M [Ge(OEt)3](Tp)(PPh3)L (9, 11). The complexes were characterised by IR and multinuclear NMR spectroscopy and by X-ray crystal structure determination of 3a
Conductance and spectroscopic mapping of EDOT polymer films upon electrochemical doping
Get PDFThis paper deals with the electrochemical doping of different poly(ethylenedioxythiophene) (PEDOT)-based active layers performed in an organic electrochemical transistor configuration through the mapping of in situ conductance trends during electrochemical doping and dedoping. The experiments are complemented by UV/Vis/NIR in situ spectroelectrochemistry in the wavelength range from 400 to 1600 nm, which allow monitoring of the development of the neutral and charged redox species. Both electropolymerized EDOT-based layers and solution-processed chemically synthesized PEDOT films are characterized. In addition to pure electropolymerized PEDOT (e-PEDOT), tris(4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)phenyl) (TPA-EDOT3) is electrodeposited to generate highly branched networks of P(TPA-EDOT3). The solution-deposited PEDOT films contain poly(ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) with ratios of 1:2.5 and 1:6. Overall, we find that e-PEDOT and PEDOT:PSS(1:2.5) behave like classical conjugated polymers with a plateau-like conductance over a wide potential region. In contrast, PEDOT:PSS(1:6) and P(TPA-EDOT3) show rather bell-shaped conductance profiles. The mixed-valence conductivity model is used to interpret the experimental results in terms of the number of accessible redox states. We suggest that the bell-shaped conductance in the case of PEDOT:PSS(1:6) is caused by a high amount of PSS insulator that limits the inter-chain interaction between PEDOT moieties and in the case of P(TPA-EDOT3) by its distorted molecular architecture
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Mitomycin C in highly myopic eyes - Author reply
No full textOphthalmology. 2005 Feb;112(2):208-18; discussion 219.
Mitomycin C modulation of corneal wound healing after photorefractive keratectomy in highly myopic eyes.
Gambato C, Ghirlando A, Moretto E, Busato F, Midena E.
SourceRefractive Surgery Service and Antimetabolite Therapy Research Unit, Department of Ophthalmology, University of Padova, Padova, Italy.
Abstract
PURPOSE: To evaluate the role of topical mitomycin C in corneal wound healing (CWH) after photorefractive keratectomy (PRK) in highly myopic eyes.
DESIGN: Prospective, double-masked, randomized clinical trial.
PARTICIPANTS: Seventy-two eyes of 36 patients affected by high (>7 diopters) myopia.
METHODS: In each patient, one eye was randomly assigned to PRK with intraoperative topical 0.02% mitomycin C application, and the fellow eye was treated with a placebo. Postoperatively, mitomycin C-treated eyes received artificial tears (3 times daily, tapered in 3 months), whereas the fellow eye was treated with fluorometholone sodium 2% and artificial tears (3 times daily, tapered in 3 months).
MAIN OUTCOME MEASURES: Uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA), contrast sensitivity, manifest refraction, and biomicroscopy. Contrast sensitivity was determined using the Pelli-Robson chart. Corneal confocal microscopy documented CWH.
RESULTS: Mean follow-up was 18 months (range, 12-36). No side effects or toxic effects were documented. At 12-month follow-up examination, UCVAs (logarithm of the minimum angle of resolution) were 0.4+/-0.48 and 0.5+/-0.53 (P = .03) in mitomycin C-treated eyes and corticosteroid-treated eyes, respectively. At 1 year, corneal haze developed in 20% of corticosteroid-treated eyes, versus 0% of mitomycin C-treated eyes. At 12, 24, and 36 months, corneal confocal microscopy showed activated keratocytes and extracellular matrix significantly more evident in untreated eyes (Ps = 0.004, 0.024, and 0.046, respectively).
CONCLUSION: Topical intraoperative application of 0.02% mitomycin C can reduce haze formation in highly myopic eyes undergoing PRK.
Comment in
Ophthalmology. 2006 Feb;113(2):357; author reply 357-8
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