Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents

Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2′-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC₅₀ value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC₅₀ value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.     

Structure-Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi

Chagas disease is a neglected parasitic disease caused by the parasitic protozoan Trypanosoma cruzi and currently affects around 8 million people. Previously, 2-isopropyl-5-(4-methoxy-3-(pyridin-3-yl)phenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0227) was discovered to be a sub-micromolar inhibitor (pIC₅₀=6.4) of T. cruzi. So far, SAR investigations of this scaffold have focused on the alkoxy substituent, the pyrazolone nitrogen substituent and the aromatic substituent of the core phenylpyrazolone. In this study, modifications of the phenyldihydropyrazolone scaffold are described. Variations were introduced by installing different substituents on the phenyl core, modifying the geminal dimethyl and installing various bio-isosteres of the dihydropyrazolone group. The anti T. cruzi activity of NPD-0227 could not be surpassed as the most potent compounds show pIC₅₀ values of around 6.3. However, valuable additional SAR data for this interesting scaffold was obtained, and the data suggest that a scaffold hop is feasible as the pyrazolone moiety can be replaced by a oxazole or oxadiazole with minimal loss of activity.     

How Consistent are Publicly Reported Cytotoxicity Data? Large‐Scale Statistical Analysis of the Concordance of Public Independent Cytotoxicity Measurements

While increased attention is being paid to the impact of data quality in cell‐line sensitivity and toxicology modeling, to date, no systematic study has evaluated the comparability of independent cytotoxicity measurements on a large‐scale. Here, we estimate the experimental uncertainty of public cytotoxicity data from ChEMBL version 19. We applied stringent filtering criteria to assemble a curated data set comprised of pIC₅₀ data for compound–cell line systems measured in independent laboratories. The estimated experimental uncertainty calculated was a mean unsigned error (MUE) value of 0.61–0.76, a median unsigned error (MedUE) value of 0.51–0.58, and a standard deviation of 0.76–1.00 pIC₅₀ units. The experimental uncertainty (σ_E) estimated from all pairs of cytotoxicity measurements with a ΔpIC₅₀ value lower than 2.5 was found to be 0.59–0.77 pIC₅₀ units, and thus 21–60 % and 21–26 % higher than that of pK_i and pIC₅₀ data for ligand–protein data (σ_E=0.47–0.48 pK_i units and σ_E=0.57‐0.61 pIC₅₀ units, respectively). The estimated σ_E value from the pairs of pIC₅₀ values measured with metabolic assays was 0.98, whereas the σ_E value was found to be 0.69 when using the 1388 pIC₅₀ pairs measured using exactly the same experimental setup. The maximum achievable Pearson correlation coefficient ( ) of in silico models trained on cytotoxicity data from different laboratories was estimated to be 0.51–0.85, which is considerably different from the value of 1 corresponding to perfect predictions, hinting at the maximum performance one can expect also from computational cytotoxicity predictions. The lowest concordance between pairs of measurements was found for the drugs paclitaxel, methotrexate, zidovudine, and docetaxel, and for the cell lines HepG2, NCI‐H460, L1210, and CCRF‐CEM, hinting at particular sensitivity of those systems to experimental setups. The highest concordance was estimated for the compound–cell line system HL‐60–etoposide (σ_E=0.70), whereas the lowest for L1210–methotrexate (σ_E=1.68). We found that annotation errors are responsible for the high discordance observed for some pairs of measurements, pointing out the importance of data curation when automatically extracting cytotoxicity data from public databases. Likewise, these results highlight the importance of estimating compound cytotoxicity with assays providing complementary biological information (i.e., metabolic, clonogenic and assays based on cell membrane integrity), especially when the mechanism of action of test compounds is unknown. From this analysis, guidelines can be created on the reliability of cytotoxicity data from public databases, which could ultimately prove valuable for modeling purposes, and to guide reporting of data in the literature.     

Synthesis of novel 2,3-condensed thieno[2,3- d ]pyrimidin-4-ones via Appel's salt chemistry

The chemistry of imino-1,2,3-dithiazoles possessing a thiophene ring with various alkyl and aromatic diamines was investigated in the expectation of obtaining novel 2,3-condensed thieno[2,3-d]pyrimidinone derivatives. Obtained via Appel's salt's (1) chemistry, methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-thiophenecarboxylate (2) is confirmed as a very interesting starting material for access to a variety of novel thiophene bioisosters of bioactive pentacyclic tetraaza-pentaphene-5, 8-diones.     

Novel Hydrophilic Riminophenazines as Potent Antiprotozoal Agents

SAR studies on a set of novel hydrophilic C-2 aminopyridinyl riminophenazines bearing variously functionalized basic side chains at C-3 were conducted. The novel compounds were evaluated for in vitro activity against two different species of Leishmania promastigotes, intramacrophage Leishmania amastigotes, chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, and also against mature-stage P. falciparum gametocytes. Their cytotoxicity was evaluated as well on BMDM cell lines. Most of the new compounds potently inhibited the growth of both genera of protozoa with IC₅₀ values in the high nanomolar range and good selectivities versus mammalian cells. Besides their potent activity against asexual intraerythrocytic stages of P. falciparum, three compounds showed potential as transmission-blocking agents. The key role of the hydrophilic C-2 aminopyridinyl substituent to improve the leishmanicidal activity and the influence of the length and the nature of the basic side chain on the antiprotozoal activity and cytotoxicity were underlined.     

Synthesis and Antitrypanosomal Activity of 1,4-Disubstituted Triazole Compounds Based on a 2-Nitroimidazole Scaffold: a Structure-Activity Relationship Study

Chagas disease affects 6–8 million people worldwide, remaining a public health concern. Toxicity, several adverse effects and inefficiency in the chronic stage of the disease are the major challenges regarding the available treatment protocols. This work involved the synthesis of twenty-two 1,4-disubstituted-1,2,3-triazole analogues of benznidazole (BZN), by using a click chemistry strategy. Analogues were obtained in moderate to good yields (40-97 %). Antitrypanosomal activity was evaluated against the amastigote forms of Trypanosoma cruzi. Compound 8 a (4-(2-nitro-1H-imidazol-1-yl)methyl)-1-phenyl-1H-1,2,3-triazole) without substituents on phenyl ring showed similar biological activity to BZN (IC₅₀=3.0 μM, SI>65.3), with an IC₅₀=3.1 μM and SI>64.5. Compound 8 o (3,4-di-OCH₃−Ph) with IC₅₀ = 0.65 μM was five-fold more active than BZN, and showed an excellent selectivity index (SI>307.7). Compound 8 v (3-NO₂, 4-CH₃−Ph) with IC₅₀=1.2 μM and relevant SI>166.7, also exhibited higher activity than BZN. SAR analysis exhibited a pattern regarding antitrypanosomal activity relative to BZN, in compounds with electron-withdrawing groups (Hammett σ+) at position 3, and electron-donating groups (Hammett σ-) at position 4, as observed in 8 o and 8 v . Further research might explore in vivo antitrypanosomal activity of promising analogues 8 a , 8 o , and 8 v . Overall, this study indicates that approaches such as the bioisosteric replacement of amide group by 1,2,3-triazole ring, the use of click chemistry as a synthesis strategy, and design tools like Craig-plot and Topliss tree are promising alternatives to drug discovery.     

Cytotoxic 1,2,3-Triazoles as Potential Leads Targeting the S100A2-p53 Complex: Synthesis and Cytotoxicity

In silico screening predicted 1 (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl) sulfonyl)-phenyl)acetamide) as an inhibitor of the S100A2-p53 protein-protein interaction. S100A2 is a validated pancreatic cancer drug target. In the MiaPaCa-2 pancreatic cell line, 1 was a ∼50 μM growth inhibitor. Synthesis of five focused compound libraries and cytotoxicity screening revealed increased activity from the presence of electron withdrawing moieties on the sulfonamide aromatic ring, with the 3,5-bis-CF₃ Library 3 analogues the most active, with GI₅₀ values of 0.91 (3-ClPh; 13 i ; BxPC-3, Pancreas) to 9.0 μM (4-CH₃; 13 d ; PANC-1, Pancreas). Activity was retained against an expanded pancreatic cancer cell line panel (MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, PANC-1 and HPAC) and the normal cell line MCF10A (breast). Bulky 4-disposed substituents on the terminal phenyl ring enhanced broad spectrum activity with growth inhibition values spanning 1.1 to 3.1 μM (4-C(CH₃)₃; 13 e ; BxPC-3 and AsPC-1 (pancreas), respectively). Central alkyl spacer contraction from propyl to ethyl proved detrimental to activity with Library 4 and 5.5- to 10-fold less cytotoxic than the propyl linked Library 2 and Library 3. The data herein was consistent with the predicted binding poses of the compounds evaluated. The highest levels of cytotoxicity were observed with those analogues best capable of adopting a near identical pose to the p53-peptide in the S100A2-p53 binding groove.     

Synthesis and Biological Evaluation of Nipecotic Acid and Guvacine Derived 1,3-Disubstituted Allenes as Inhibitors of Murine GABA Transporter mGAT1

A new class of nipecotic acid and guvacine derivatives has been synthesized and characterized for their inhibitory potency at mGAT1–4 and binding affinity for mGAT1. Compounds of the described class are defined by a four-carbon-atom allenyl spacer connecting the nitrogen atom of the nipecotic acid or guvacine head with an aromatic residue. Among the compounds investigated, the mixture of nipecotic acid derivatives rac-{(R_a)-1-[4-([1,1′:2′,1′′-terphenyl]-2-yl)buta-2,3-dien-1-yl](3R)-piperidine-3-carboxylic acid} and rac-{(S_a)-1-[4-([1,1′:2′,1′′-terphenyl]-2-yl)buta-2,3-dien-1-yl](3R)-piperidine-3-carboxylic acid} ( 21 p ), possessing an o-terphenyl residue, was identified as highly selective and the most potent mGAT1 inhibitor in this study. For the (R)-nipecotic acid derived form of 21 p , the inhibitory potency in [³H]GABA uptake assays was determined as pIC₅₀=6.78±0.08, and the binding affinity in MS Binding Assays as pK_i=7.10±0.12. The synthesis of the designed compounds was carried out by a two-step procedure, generating the allene moiety via allenylation of terminal alkynes which allows broad variation of the terminal phenyl and biphenyl subunit.     

Orthoamide. L. Beiträge zur Chemie von Propiolaldehydaminalen – Synthesen und Umsetzungen zu Push–Pull-substituierten Buta-1,3-dienen,Cyclobutanen sowie vinylogen Amidiniumsalzen und 1,2,3-Triazolen

Orthoamides. L. Contribution to the Chemistry of Propiolaldehydaminales – Synthesis and Transformations to Push–Pull-substituted Buta-1,3-dienes, Cyclobutanes, Vinylogous Amidinium Salts and 1,2,3-Triazoles Tert-butylaminalester 5 reacts with terminal alkynes to give aminals of substituted propiolaldehydes 3c, d . The aminal 3a is accessible from N,N,N′,N′-tetramethylformamidinium chloride (7b) and sodium acetylide. The aminals 3b,c can also be prepared from bis(dimethylamino)acetonitrile 8 and terminal alkynes in the presence of sodium hydride. The nitrile 8 is also useful for the preparation of the bis-aminal of acetylenedialdehyde 6 . The aminal 3e can be transaminated by heating with secondary amines to give the aminals 3f–i . The aminals 3a–i react with strong CH₂-acidic compounds (pK_a between 9 and 14) to give the 1-dialkylamino-1,3-butadienes 10 . The isomeric 1-dialkylamino-butadienes 18 can be obtained from the condensation of the CH-acidic cinnamic acid derivatives 19 with dimethylformamidedimethylacetal. CH and NH-acidic compounds as cyanacetamide react with the aminals 3c,e exclusively with the acidic methylene group to produce the enamines 10h,t . The acylformamidine 21 can be obtained from 10t and tert-butylaminalester 5 . The pyridone 22 is accessible from the condensation product 10h by thermal cyclization. The pyrido[2,3-d]pyrimidine 26 is formed in the reaction of the 6-amino-uracile 23 with the aminal 3a . In an unexpected reaction the 1,2-bis(cyano-dialkylaminomethylene)-cyclobutanes 28a–d result from the action of trimethylsilylcyanide on the aminals 3e–h . The corresponding reaction with trimethylsilylisothiocyanate affords the vinylogous amidinium thiocyanates 34a, b . In the reaction of trimethylsilylazide and the aminals 3 are produced the 4-(dialkylaminomethylene)-4H-1,2,3-triazoles 38 .     

6,7‐Dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinolines as Superior Reversal Agents for P‐Glycoprotein‐Mediated Multidrug Resistance

P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7‐dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2‐[(1‐{4‐[2‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]phenyl}‐1H‐1,2,3‐triazol‐4‐yl)methoxy]‐N‐(p‐tolyl)benzamide (compound 7 h ) was identified as a potent modulator of P‐gp‐mediated MDR, with high potency (EC₅₀=127.5±9.1 nM ), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR‐related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P‐gp‐mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P‐gp‐mediated MDR that has good potential for further development.     

Synthesis and Biological Evaluation of Ferrocenylquinoline as a Potential Antileishmanial Agent

The emergence of resistance against antileishmanial drugs in current use necessitates the search for new classes of antileishmanial compounds. Herein we report the design, synthesis, and evaluation of a novel ferrocenylquinoline for activity against Leishmania donovani. 7‐Chloro‐N‐[2‐(1H‐5‐ferrocenyl‐1,2,3‐triazol‐1‐yl)ethyl]quinolin‐4‐amine ( 1 ) was generated by coupling an iron(II) ethynylferrocene species with 4‐(2‐ethylazido)amino‐7‐chloroquinoline using click chemistry. The synthesized compound 1 was tested for its antileishmanial activity using both promastigote and amastigote stages of L. donovani. Compound 1 showed promising anti‐promastigote activity, with an IC₅₀ value of 15.26 μM and no cytotoxicity toward host splenocytes. From the battery of tests conducted in this study, it appears that this compound induces parasite death by promoting oxidative stress and depolarizing the mitochondrial membrane potential, thereby triggering apoptosis. These results suggest that ferrocenylquinoline 1 is a suitable lead for the development of new antileishmanial drugs.     

Synthesis and Pharmacological Evaluation of σ2 Receptor Ligands Based on a 3-Alkoxyisoxazole Scaffold: Potential Antitumor Effects against Osteosarcoma

Since its initial discovery as the basis for nicotinic acetylcholine receptor ligands, the 3-alkoxyisoxazole scaffold has been shown to be a versatile platform for the development of potent σ1 and σ2 receptor ligands. Herein we report a further SAR exploration of the 3-alkoxyisoxazole scaffold with the aim of obtaining potent σ2 receptor ligands. Various substitutions on the benzene ring and at the basic amino regions resulted in a total of 21 compounds that were tested for their binding affinities for the σ2 receptor. In particular, compound 51 [(2S)-1-(4-ammoniobutyl)-2-(((5-((3,4-dichlorophenoxy)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-ium chloride] was identified as one of the most potent σ2 ligands within the series, with a K_i value of 7.9 nM. It demonstrated potent antiproliferative effects on both osteosarcoma cell lines 143B and MOS−J (IC₅₀ values of 0.89 and 0.71 μM, respectively), relative to siramesine (IC₅₀ values of 1.81 and 2.01 μM). Moreover, compound 51 inhibited clonal formation of osteosarcoma 143B cells at 1 μM, corresponding to half the dose required of siramesine for similar effects. The general cytotoxicity profile of compound 51 was assessed in a number of normal cell lines, including HaCaT, HAF, and LO2 cells. Furthermore, FACS analysis showed that compound 51 likely inhibits osteosarcoma cell growth by disruption of the cell cycle and promotion of apoptosis.     

Novel Very Long-Chain α-Methoxylated Δ5,9 Fatty Acids from the Sponge Asteropus niger Are Effective Inhibitors of Topoisomerases IB

The novel fatty acids (2R,5Z,9Z)‐2‐methoxy‐25‐methyl‐5,9‐hexacosadienoic acid ( 1a ) and (2R,5Z,9Z)‐2‐methoxy‐24‐methyl‐5,9‐hexacosadienoic acid ( 1b ) were isolated in 80 % purity from the Caribbean sponge Asteropus niger by chloroform/methanol extraction followed by solvent partitioning and silica gel column chromatography. The compounds were characterized by utilizing a combination of gas chromatography‐mass spectrometry, nuclear magnetic resonance, and circular dichroism. Acids 1a and 1b were not detected in the phospholipids (PtdCho and PtdIns) of the sponge, but rather as free FA and possibly in glycosylceramides. The mixtures of 1a and 1b displayed cytotoxicity towards THP‐1 and HepG2 cells with EC_50's between 41 and 35 μg/mL. Apoptosis was not the preferred mode of cell death induced by 1a – 1b in the THP‐1 cells. This implies other types of cytotoxicity mechanisms, such as membrane disruption and/or the inhibition (EC₅₀ = 1.8 μg/mL) of the human topoisomerase IB enzyme (hTopIB), with a mechanism of inhibition different from the one displayed by camptothecin (CPT). In a separate experiment, the mixture of 1a and 1b also displayed cytotoxicity towards ex vivo mouse splenocytes infected with Leishmania infantum amastigotes (IC₅₀ = 0.17 mg/mL) and free living promastigotes (IC₅₀ = 0.34 mg/mL). It was also found that the FA were inhibitory of the Leishmania topoisomerase IB (LTopIB) with an EC₅₀ = 5.1 μg/mL. Taken together, 1a and 1b represent a new class of FA with potential as TopIB inhibitors that preferentially inhibit hTopIB over LTopIB.     

Different Binding Modes of Small and Large Binders of GAT1

Well‐known inhibitors of the γ‐aminobutyric acid (GABA) transporter GAT1 share a common scaffold of a small cyclic amino acid linked by an alkyl chain to a moiety with two aromatic rings. Tiagabine, the only FDA‐approved GAT1 inhibitor, is a typical example. Some small amino acids such as (R)‐nipecotic acid are medium‐to‐strong binders of GAT1, but similar compounds, such as proline, are very weak binders. When substituted with 4,4‐diphenylbut‐3‐en‐1‐yl (DPB) or 4,4‐bis(3‐methylthiophen‐2‐yl)but‐3‐en‐1‐yl (BTB) groups, the resulting compounds have similar pK_i and pIC₅₀ values, even though the pure amino acids have very different values. To investigate if small amino acids and their substituted counterparts share a similar binding mode, we synthesized butyl‐, DPB‐, and BTB‐substituted derivatives of small amino acids. Supported by the results of docking studies, we propose different binding modes not only for unsubstituted und substituted, but also for strong‐ and weak‐binding amino acids. These data lead to the conclusion that following a fragment‐based approach, not pure but N‐butyl‐substituted amino acids should be used as starting points, giving a better estimate of the activity when a BTB or DPB substituent is added.     

Mechanosynthesis of Triazolyl-bis(indolyl)methane Pharmacophores via Gold Catalysis: A Prelude to Their Molecular Electronic Properties and Biological Potency

Chemical structures possessing both 1,2,3-triazole and bis(indolyl)methane fragments gained considerable interest in drug synthesis owing to their established biological efficacies. However, 1,2,3-triazoles linked at the bridging position of bis(indolyl)methane is a logical and unexplored design approach. In this regard, nine new triazolyl-bis(indolyl)methane conjugates under AuCl catalyzed ball-milling conditions were accomplished. Comparative evaluation on absorptive and emissive properties of the synthesized dyads were also analyzed. To unravel the influence of different peripheral substituents on the electronic structure and π-orbital properties, theoretical investigations were performed. Screening of molecules for free radical scavenging, anti-inflammatory and antidiabetic showed comparable potency against reference drugs. In particular, compounds 7 h , 7 d and 7 a displayed good efficiency of α-amylase inhibition. The DNA gyrase inhibitory potential of all compounds were assessed in silico which revealed high binding affinity (ΔG=−8.99 Kcal/mol) for 7 i followed by 7 h (ΔG=−7.80 Kcal/mol) with the targeted protein.     

Synthesis and anticorrosion properties of poly(2,3‐dimethylaniline) doped with phosphoric acid

Poly(2,3‐dimethylaniline) (P(2,3‐DMA)) was synthesized chemically by using phosphoric acid (H₃PO₄) as protonic acid. The optimum ratio for n(H₃PO₄)/n(2,3‐DMA)/n(APS) was 2.5/1/2, and the optimum temperature was 30°C. The spectra of ultraviolet‐visible and infrared demonstrate that the structure of P(2,3‐DMA) was similar with polyaniline (PANI) except for the 2,3‐ortho‐substitute methyl. The result of X‐ray diffraction and solubility analysis indicate that owing to the 2,3‐ortho‐substitute benzene ring, the P(2,3‐DMA) has poorly partial crystallinity and better solubility. In addition, the anticorrosion property of P(2,3‐DMA) was better than PANI. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Design and Synthesis of Tricyclic JAK3 Inhibitors with Picomolar Affinities as Novel Molecular Probes

The Janus kinase (JAK) signaling pathway is of particular importance in the pathology of inflammatory diseases and oncological disorders, and the inhibition of Janus kinase 3 (JAK3) with small molecules has proven to provide therapeutic immunosuppression. A novel class of tricyclic JAK inhibitors derived from the 3‐methyl‐1,6‐dihydrodipyrrolo[2,3‐b:2′,3′‐d]pyridine scaffold was designed based on the tofacitinib–JAK3 crystal structure by applying a rigidization approach. A convenient synthetic strategy to access the scaffold via an intramolecular Heck reaction was developed, and a small library of inhibitors was prepared and characterized using in vitro biochemical as well as cellular assays. IC₅₀ values as low as 220 pM could be achieved with selectivity for JAK3 over other JAK family members. Both activity and selectivity were confirmed in a cellular STAT phosphorylation assay, providing also first‐time data for tofacitinib. Our novel inhibitors may serve as tool compounds and useful probes to explore the role of JAK3 inhibition in pharmacodynamics studies.     

Cyclopentadienyl-Based Anticancer Drugs: Improvement of Cytotoxic Activity through Functionalisation of the π Ligand

Cytotoxic complexes containing molybdenum are widely studied as a potential substitution for commercially used drugs that often suffer from pronounced side effects and cellular resistance. Compounds of the type [(η⁵-Cp′)Mo(CO)₂(^N,NL)][BF₄], where Cp is cyclopentadienyl and ^N,NL is a bidentate ligand, are well known for their strong anticancer activity. It is a generally accepted paradigm that the nature of the coordinated ^N,NL ligand has a major impact on the cytotoxicity. In this study, a series of new functionalised Cp complexes of molybdenum was synthesised from derivatised fulvenes as π-ligand precursors. Indeed, the coordination sphere‘s modulation by various N,N-chelating ligands afforded species active toward leukemic cell line MOLT-4 with IC₅₀ values depending on the character of the N,N-chelator used. However, following study clearly showed that functionalisation of the Cp ring with an amine moiety considerably improved cytotoxicity. These results are of crucial importance for the future design of highly active cytotoxic drugs, as modification of cyclopentadienyl is believed to have a minor effect on biological activity.     

A New Class of 1‐Aryl‐5,6‐dihydropyrrolo[2,1‐a]isoquinoline Derivatives as Reversers of P‐Glycoprotein‐Mediated Multidrug Resistance in Tumor Cells

A number of aza‐heterocyclic compounds, which share the 5,6‐dihydropyrrolo[2,1‐a]isoquinoline (DHPIQ) scaffold with members of the lamellarin alkaloid family, were synthesized and evaluated for their ability to reverse in vitro multidrug resistance in cancer cells through inhibition of P‐glycoprotein (P‐gp) and/or multidrug‐resistance‐associated protein 1. Most of the investigated DHPIQ compounds proved to be selective P‐gp modulators, and the most potent modulator, 8,9‐diethoxy‐1‐(3,4‐diethoxyphenyl)‐3‐(furan‐2‐yl)‐5,6‐dihydropyrrolo[2,1‐a]isoquinoline‐2‐carbaldehyde, attained sub‐micromolar inhibitory potency (IC₅₀: 0.19 μm ). Schiff bases prepared by the condensation of some 1‐aryl‐DHPIQ aldehydes with p‐aminophenol also proved to be of some interest, and one of them, 4‐((1‐(4‐fluorophenyl)‐5,6‐dihydro‐8,9‐dimethoxypyrrolo[2,1‐a]isoquinolin‐2‐yl)methyleneamino)phenol, had an IC₅₀ value of 1.01 μm . In drug combination assays in multidrug‐resistant cells, some DHPIQ compounds, at nontoxic concentrations, significantly increased the cytotoxicity of doxorubicin in a concentration‐dependent manner. Studies of structure–activity relationships and investigation of the chemical stability of Schiff bases provided physicochemical information useful for molecular optimization of lamellarin‐like cytotoxic drugs active toward chemoresistant tumors as well as nontoxic reversers of P‐gp‐mediated multidrug resistance in tumor cells.     

Indeno-Polycyclic Aromatic Hydrocarbons: A Versatile New Synthetic Route

Acylation of a polycyclic aromatic hydrocarbon (PAH) adjacent to a ring junction with 2-bromobenzoyl chloride followed by Flash Vacuum Pyrolysis (FVP) of the resulting bromoketone affords the corresponding indeno-annulated PAH. The new method is illustrated by syntheses of indeno[1,2,3-cd]pyrene (1) from pyrene and indeno[1,2,3-cd]fluoranthene (2) from fluoranthene. The formation of indeno[1,2,3,4-defg]chrysene (11) from FVP of 8-(2-bromobenzoyl)-fluoranthene (10), and as a secondary product from FVP of 3-(2-bromobenzoyl)fluoranthene (9), reveals the ability of phenyl groups to migrate around the periphery of a didehydro-PAH. Mechanisms involving reversible hydrogen atom transfers are proposed. Diacylation of fluoranthene with 2-bromobenzoyl chloride followed by FVP gives the previously unknown, nonplanar, nonalternant, C₂₈H₁₄ PAH diindeno[1,2,3,4-defg: 1,2,3-rs]chrysene (21) in just two steps.