Tertiary Hydroxy Research Articles

Development of camptothecin nano-prodrugs based on trimethyl lock groups toward selective drug release in cancer cells

Selective drug release at the tumor site contributes to the reduction of side effects caused by anticancer treatments. To achieve a selective drug release system in cancer cells, we designed a new prodrug in which the anticancer drug camptothecin (CPT) is linked to a trimethyl lock (TML) group by an ester bond. Evaluation of in vitro cytostatic activity and drug release kinetics of the CPT-TML nano-prodrugs revealed that the ester of CPT-TML was stable against hydrolysis due to the steric hindrance around the ester derived from the tertiary hydroxy group. In contrast, CPT was smoothly released via sterically hindered ester cleavage by lactonization of the activated TML group. This finding will help in the development of nano-prodrugs with high selectivity at tumor site.

Noncanonical Strigolactone Analogues Highlight Selectivity for Stimulating Germination in Two Phelipanche ramosa Populations.

Strigolactones (SLs) are plant hormones exuded in the rhizosphere with a signaling role for the development of arbuscular mycorrhizal (AM) fungi and as stimulants of seed germination of the parasitic weeds Orobanche, Phelipanche, and Striga, the most threatening weeds of major crops worldwide. Phelipanche ramosa is present mainly on rape, hemp, and tobacco in France. P. ramosa 2a preferentially attacks hemp, while P. ramosa 1 attacks rapeseed. The recently isolated cannalactone (14) from hemp root exudates has been characterized as a noncanonical SL that selectively stimulates the germination of P. ramosa 2a seeds in comparison with P. ramosa 1. In the present work, (-)-solanacol (5), a canonical orobanchol-type SL exuded by tobacco and tomato, was established to possess a remarkable selective germination stimulant activity for P. ramosa 2a seeds. Two cannalactone analogues, named (±)-SdL19 and (±)-SdL118, have been synthesized. They have an unsaturated acyclic carbon chain with a tertiary hydroxy group and a methyl or a cyclopropyl group instead of a cyclohexane A-ring, respectively. (±)-SdL analogues are able to selectively stimulate P. ramosa 2a, revealing that these minimal structural elements are key for this selective bioactivity. In addition, (±)-SdL19 is able to inhibit shoot branching in Pisum sativum and Arabidopsis thaliana and induces hyphal branching in the AM fungus Rhizophagus irregularis, like SLs.

Exploration of Oxidative Ritter-Type Reaction of α-Arylketones and Its Application for the Collective Total Syntheses of Erythrina Alkaloids

Exploration of Oxidative Ritter-Type Reaction of α-Arylketones and Its Application for the Collective Total Syntheses of <i>Erythrina</i> Alkaloids

Access to enantioenriched compounds bearing challenging tetrasubstituted stereocenters via kinetic resolution of auxiliary adjacent alcohols

Contemporary asymmetric catalysis faces huge challenges when prochiral substrates bear electronically and sterically unbiased substituents and when substrates show low reactivities. One of the inherent limitations of chiral catalysts and ligands is their incapability in recognizing prochiral substrates bearing similar groups. This has rendered many enantiopure substances bearing several similar substituents inaccessible. Here we report the rationale, scope, and applications of the strategy of kinetic resolution of auxiliary adjacent alcohols (KRA*) that can be used to solve the above troubles. Using this method, a large variety of optically enriched tertiary alcohols, epoxides, esters, ketones, hydroxy ketones, epoxy ketones, β-ketoesters, and tetrasubstituted methane analogs with two, three, and four spatially and electronically similar groups can be readily obtained (totally 96 examples). At the current stage, the strategy serves as the optimal solution that can complement the inability caused by direct asymmetric catalysis in getting chiral molecules with challenging fully substituted stereocenters.

Stereocontrolled syntheses of (-)- and (+)-γ-diisoeugenol along with optically active eight stereoisomers of 7,8'-epoxy-8,7'-neolignan.

It was shown that reduction of the tertiary benzylic hydroxy group of (2R,3S,4R,5S)-3,5-bis(4-benzyloxy-3-methoxyphenyl)-2,4-dimethyltetrahydro-3-furanol 17 followed by the intramolecular Friedel-Crafts reaction gave exclusively indane with (7S,7'S,8R,8'R)-2,7'-cyclo-7,8'-neolignan structure 18 along with (7S,7'R,8S,8'R)-7,8'-epoxy-8,7'-neolignan structure 19. Indane 18 was converted to (-)-γ-diisoeugenol ((-)-4). On the other hand, (2S,3R,4R,5S)-3,5-bis(4-benzyloxy-3-methoxyphenyl)-2,4-dimethyltetrahydro-3-furanol 22 did not afford indane, but the tetrahydrofuran structure with (7S,7'S,8S,8'S)-7,8'-epoxy-8,7'-neolignan structure 23 and 7'-epi-23.

Design and synthesis of novel quinic acid derivatives: invitro cytotoxicity and anticancer effect on glioblastoma.

Aim: Quinic acid (QA) is a cyclic polyol exhibiting anticancer properties on several cancers. However, potential role of QA derivatives against glioblastoma is not well established. Methodology & results: Sixteennovel QA derivatives and QA-16 encapsulated poly (lactic-co-glycolic acid)nanoparticles (QA-16-NPs) were screened for their anti-glioblastoma effect using standard cell and molecular biology methods. Presence of a tertiary hydroxy and silylether groups in the lead compound were identified for the antitumor activity. QA-16 have 90% inhibition with the IC50 of 10.66μM and 28.22μM for LN229 and SNB19, respectively. The induction of apoptosis is faster with the increased fold change of caspase 3/7 and reactive oxygen species. Conclusion: QA-16 and QA-16-NPs shows similar cytotoxicity effect, providing the opportunity to use QA-16 as a potential chemotherapeutic agent.

Vibrational circular dichroism behavior of quinol cacalolides from Psacalium aff. sinuatum

In search to find levels of density functional theory (DFT) for the accurate prediction of vibrational circular dichroism (VCD) spectra of cacalolides, we undertook the evaluation of isomeric quinols. To gain compounds that provide experimental VCD spectra for comparative purposes to the calculated spectra, we prepared the hexanes extracts of the roots of Psacalium aff. sinuatum (Cerv.) H. Rob. & Brettell. They afforded the known furotetralin cacalol (1a), the isomeric quinols cacalone (2a) and epi‑cacalone (3a), and the furodehydrotetralin cacalohastine (4). In an earlier work we found that the absolute configuration (AC) determination of 1a by VCD required the study of its acetyl derivative 1b when comparing the experimental data with DFT spectra calculated at the commonly used B3LYP/DGDZVP level of theory. Herein the AC of acetylcacalone (2b) and of non-acetylated 3a were addressed using the same VCD methodology for which it is difficult to predict which DFT level of theory would provide satisfactory results for the uncommon quinol chromophores. It turned out that epi‑cacalone (3a) required the B3PW91/DGDZVP2 level of theory, while in the case of natural occurring 2a it was necessary, as in the case of 1a, to study the acetyl derivative 2b since in 2a the tertiary hydroxy group is prone to intermolecular associations in solution. In addition, the dihydronaphthofuran 4 required the PBEPBE/DGDZVP level of theory, mainly used for aromatic compounds, to be modeled satisfactorily.

Synthesis of 13,14-Dehydro-15-deoxy-16-hydroxy-16-methyl-17-phenoxyprostaglandin B1 Ethyl Ester

A new synthetic route has been developed for the construction of the main skeleton of ω-aryloxyprostaglandin (PG) via 1,2-addition of lithiated 3-methyl-3-(trimethylsilyloxy)pent-1-yne to the ketone carbonyl group of ethyl 7-(5-oxocyclopent-1-en-1-yl)heptanoate. The addition reaction was accompanied by the formation of cyclopentenone dimer as minor product. The 1,2-adduct containing a tertiary hydroxy group was oxidized with pyridinium chlorochromate to 13-dehydro-PGB1 ethyl ester.

Glycosylation with ulosonates under Mitsunobu conditions: scope and limitations

Mitsunobu reactions on highly hindered tertiary type hydroxy groups of ulosonates: from 47 NuH compounds O-, N-, and S-nucleophiles gave the corresponding ulosidonates in 30–78% yields, while C-nucleophiles were unreactive.

Alcohol-Directed ortho-C–H Alkenylation

We report a simple and mild dehydrogenative cross-coupling reaction of unprotected arylethanols and acrylates. Unlike the case of previous reactions, in which prior functionalization of the substrate with a metal-coordinating site was required, free primary, secondary, or tertiary hydroxy groups were found to be effective directing groups for the ortho-C–H palladation and subsequent olefination.

Synthesis of Imidazo[1,2‐a]pyridines and Imidazo[2,1‐b]thiazoles Attached to a Cycloalkyl or Saturated Heterocycle Containing a Tertiary Hydroxy Substitution

A new method has been developed for the synthesis of imidazo[1,2‐a]pyridines, imidazo[2,1‐b]thiazoles, and benzo[d]imidazo[2,1‐b]thiazoles attached to a cycloalkyl or saturated heterocycle containing a tertiary hydroxy substitution. Readily available substituted 2‐aminopyridines, 2‐aminothiazoles, and 2‐aminobenzothiazoles were treated with bromohydroxycycloalkyl ethanones to afford the desired products in good yields.

Total Synthesis of (-)-Ambiguine P.

Described is a concise total synthesis of (-)-ambiguine P, a cycloheptane-containing member of the hapalindole alkaloids. The challenging pentacyclic framework of the natural product was assembled rapidly via a [4 + 3] cycloaddition reaction-inspired strategy, and the tertiary hydroxy group was introduced by an NBS-mediated bromination-nucleophilic substitution sequence.

New facilities of Biginelli reaction. Synthesis of methyl 6-aryl-5-benzoyl-4-methoxy-2-oxohexahydropyrimidine-4-carboxylates

Three-component reaction of methyl benzoylpyruvate, aromatic aldehyde, and urea in methanol in the presence of sodium bisulfate stops at the stage of the formation of nondehydrated product with a methylated tertiary hydroxy group and results in methyl 6-aryl-5-benzoyl-4-methoxy-2-oxohexahydropyrimidine-4-carboxylates.

Callistemenonone A, a novel dearomatic dibenzofuran-type acylphloroglucinol with antimicrobial activity from Callistemon viminalis

A new acylphloroglucinol with a novel architecture including an unprecedented dearomatic dibenzofuran core, named callistemenonone A (1), was isolated from the leaves of Callistemon viminalis (Myrtaceae). The structure was fully characterized on the basis of extensive spectroscopic analysis, including UV, HRESIMS, as well as 1D and 2D NMR spectral data (HSQC, HMBC, and ROESY). The deduced structure represents the first example of a natural dibenzofuran with two phenyl moieties coupling through tertiary hydroxy and ketal carbons. A plausible biogenetic pathway involving oxidative coupling and dearomatization as key steps is proposed to account for the biosynthesis of this novel class of dibenzofuran. Moreover, antimicrobial assays, in conjunction with the time-killing and biophysical studies, revealed that 1 exerted potent bactericidal activity against a panel of methicillin resistant pathogenic microbes with a unique mechanism.

Cis-Diastereoselective synthesis of chroman-fused tetralins as B-ring-modified analogues of brazilin.

We have synthesized a series of cis-6a,7,8,12b-tetrahydro-6H-naphtho[2,1-c]chromen-6a-ols as B-ring-modified analogues of (±)-brazilin. A completely regio- and cis-diastereoselective intramolecular Friedel–Crafts epoxy–arene cyclization of 1-tetralone-derived glycidyl ethers catalyzed by Brønsted acids was used as the key step. Our worries concerning the formation of cis–trans product mixtures and their probable conversion to naphthopyran derivatives via dehydration of the tertiary hydroxy group were laid to rest. Additionally, the angular hydroxy group of one of the synthesized products has been reductively removed by a diastereoselective method which should be useful in future for preparing libraries of chroman-fused tetralins with trans-stereochemistry at the ring junction.

Alkoxyallene-ynes: Selective Preparation of Bicyclo[5.3.0] Ring Systems Including a δ-Alkoxy Cyclopentadienone.

The development of an intramolecular rhodium(I)-catalyzed Pauson-Khand reaction of alkoxyallene-ynes with a proximal alkoxy group is reported. This reaction, in the presence of a [Rh(cycloocta-1,5-diene)Cl]2/propane-1,3-diylbis(diphenylphosphane) system under a CO atmosphere, constitutes a powerful tool for selectively accessing carbo- and heterobicyclo[5.3.0] frameworks featuring an enol ether moiety. Through this procedure, a straightforward access to guaiane skeletons with a tertiary hydroxy group at the C10 position was achieved.

Iodine(III)‐Catalyzed Rearrangements of Imides: A Versatile Route to α,α‐Dialkylated α‐Hydroxy Carboxylamides

A tertiary hydroxy group α to a carboxyl moiety comprises a key structural motif in many bioactive substances. With the herein presented metal-free rearrangement of imides triggered by hypervalent λ(3)-iodane, an easy and selective way to gain access to such a compound class, namely α,α-disubstituted-α-hydroxy carboxylamides, was established. Their additional methylene bromide side chain constitutes a useful handle for rapid diversification, as demonstrated by a series of further functionalizations. Moreover, the in situ formation of an iodine(III) species under the reaction conditions was proven. Our findings clearly corroborate that hypervalent λ(3)-benziodoxolones are involved in these organocatalytic reactions.

Chromatographic characteristics of α-alkynols

Chromatographic retention indices on a standard nonpolar poly(dimethylsiloxane) phase were determined for 33 α-alkynols and their 27 dehydration products (conjugated alkenynes). The resulting data are proposed to be verified using the retention indices of acetylenic alcohols estimated by the additive scheme from the retention indices of isostructural alkynes with the inclusion of increments for secondary and tertiary hydroxy groups. The analogous approach to data the verification of data for alkenynes is based on correlation of their retention indices with normal boiling points.

Tertiary Alcohols as Substrates for SN2‐Like Stereoinversion

Rewrite the textbooks! The stereospecific bimolecular substitution reaction (SN 2) is usually limited to primary and secondary electrophiles. The Shenvi group has developed a method in which tertiary alcohol substrates are converted into isocyanides with configurational inversion. Intriguingly, tertiary hydroxy groups react selectively in the presence of unprotected primary and secondary hydroxy groups.

Synthesis of (±)-lecanindole D

The first synthesis of the racemate of lecanindole D, an indole sesquiterpenoid with potent and selective agonist activity toward the progesterone receptor, has been achieved from a known tetracyclic alcohol by using a diastereoselective installation of its tertiary hydroxy group via an epoxide intermediate and a Pd(II)-mediated construction of the indole ring moiety as the key transformations.