Synthesis and cytotoxic evaluation of C-9 oxidized podophyllotoxin derivatives

A series of podophyllotoxin and podophyllic aldehyde derivatives, lacking the lactone ring and oxidized at C-9 position, has been prepared. The functionalities considered at C-9 were carboxylic acids and several derivatives such as esters, amides, nitriles or anhydrides. The synthesized compounds were cytotoxic at the micromolar level, though less potent and selective than the parent compounds, revealing the influence of the C-9 electrophilic character on the potency and selectivity of these cyclolignans.     

Syntheses of 4,6'-epoxymorphinan derivatives and their pharmacologies

A modification of the message site in the skeleton of naltrexone was carried out to improve the potency and selectivity of the compound for an opioid receptor subtype. In the course of conversion, we synthesized 7-membered ring ether derivatives, which had an inserted OCH(2) group between 4- and 6-positions of morphinan skeleton. One of the 7-membered ring ether derivatives possessed more potent antagonistic activity than naltrexone for the mu opioid receptor. Another compound possessing 17-methyl group derived from noroxycodone may be a mu opioid receptor partial agonist and showed analgesic activity. We are currently examining the subtype selectivity of these compounds.     

Synthesis and evaluation of novel podophyllotoxin analogs

Because prior studies have shown inconsistency between structure-activity relationships for podophyllotoxin derivatives as topoisomerase II inhibitors and cytotoxic agents, eight novel podophyllotoxin analogs were synthesized to further explore the effects of structural variations on both A and D rings on activity. The new compounds contain a 4,5-dimethoxy substituted A ring and opened D-ring variants and were prepared by appropriate functional and stereochemical operations at the methylenedioxy group, C7, C8, and C8'. Four compounds (15, 18, 21 and 22) demonstrated noticeable inhibitory activity against A549, DU145, KB and KBvin tumor cells, and the most active compound 18 showed IC(50) values less than 10 μg/mL.     

Synthesis and biological evaluation of 4,5-dihydro-1H-pyrazole derivatives as potential nNOS/iNOS selective inhibitors. Part 2: Influence of diverse substituents in both the phenyl moiety and the acyl group

In a preliminary article, we reported a series of 4,5-dihydro-1H-pyrazole derivatives as neuronal nitric oxide synthase (nNOS) inhibitors. Here we present the data about the inhibition of inducible nitric oxide synthase (iNOS) of these compounds. In general, we can confirm that these pyrazoles are nNOS selective inhibitors. In addition, taking these compounds as a reference, we have designed and synthesized a series of new derivatives by modification of the heterocycle in 1-position, and by introduction of electron-donating or electron-withdrawing substituents in the aromatic ring. These derivatives have been evaluated as nNOS and iNOS inhibitors in order to identify new compounds with improved activity and selectivity. Compound 3r, with three methoxy electron-donating groups in the phenyl moiety, is the most potent nNOS inhibitor, showing good selectivity nNOS/iNOS.     

Design,Synthesis and Pharmacological Evaluation of New Anticancer Fused Pentacycles

The quinoline chromophore has long formed the basis for the clinical development of novel antitumour agents. Camptothecin derivatives have already proved their clinical efficacy and compounds such as ascididemin (pyridoacridine family), DHDMC (protoberberine family) have a very promising future. During our search for new cytotoxic molecules, we have designed compounds based on the benzo[c]pyrido[2,3,4-kl]acridine skeleton which combines the structural features of ascididemin and DHDMC. Corresponding compounds were synthesized and evaluated for their cytotoxic activity against human prostatic PC-3 cell lines. Some have shown promising biological activity in inhibiting the growth of cell lines which are resistant to camptothecin.     

Different strategies for the chemical synthesis of lignans

This paper summarises the results of three projects. The first is concerned with developing general routes for the synthesis of lignans. In particular, two routes involving tandem conjugate addition reactions and Diels Alder reactions respectively that have been used to synthesise podophyllotoxin derivatives are described. The second project is concerned with the asymmetric synthesis of lignans and involves the application of these reactions, with the introduction of a menthyloxy group as a chiral auxiliary, to achieve the asymmetric synthesis of podophyllotoxin derivatives. The third project is concerned with the attempted biomimetic syntheses of podophyllotoxin derivatives using oxidative coupling reactions. Attention is focussed primarily on the use of hypervalent iodine reagents, which yield stegane and isostegane derivatives rather than podophyllotoxin derivatives. Other examples of biaryl coupling leading to stegane and isostegane derivatives are included, and other examples of lignan synthesis involving hypervalent iodine reagents are also described. Abbreviations: DDQ – 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DMAD – dimethyl acetylenedicarboxylate (dimethyl butynedioate); PIDA – phenyliodonium diacetate, iodobenzene diacetate; PIFA – phenyliodonium bis(trifluoroacetate), [bis(trifluoroacetoxy) iodobenzene]; Ra-Ni – Raney nickel; TBAF – tetrabutylammonium fluoride; TBDMS –t-butyldimethylsilyl; TFA – trifluoroacetic acid; TFAA – trifluoroacetic anhydride; TFE – 2,2,2-trifluoroethanol; TTFA – thallium(III) trifluoroacetate.     

Podophyllotoxin: Current approaches to its biotechnological production and future challenges

Many plant‐derived agents are being used to treat cancer, including taxol, vinblastine, vincristine, or camptothecin and podophyllotoxin derivatives, among others. Plant biotechnology can provide a new tool for the production of anticancer agents but in spite of considerable efforts to produce vinblastine and vincristine in cell cultures and knowledge of the biosynthetic pathway of Catharanthus roseus alkaloids, the biotechnological production of taxol has only been achieved at an industrial level by companies such as Phyton Biotech and Cytoclonal Pharmaceutics. Podophyllotoxin was isolated as the active antitumor agent from the roots of Podophyllum species and more recently from the genus Linum and others. Etoposide, teniposide, and etophos are semi‐synthetic derivatives of podophyllotoxin and are used in the treatment of cancer. Biotechnological approaches, including the use of cell cultures, biotransformation, or metabolic engineering techniques to manipulate the biosynthetic pathway, represent an alternative for the production of podophyllotoxin and are discussed in this review.     

Preparation and characterization of novel pyrrol-3-ones attached to α/β-amino acids, esters and amides

Summary. Various α/β amino acid derivatives 5 were attached to compounds 3 to yield 2,3-dihydro-1H-pyrrol-3-ones amino acids derivatives 6. This rare heterocyclic amino acid skeleton including the pyrrolo[1,2-b][1,3]oxazol moiety was also successfully prepared in the esteric form. The structure of the new compounds was characterized by spectroscopic methods.     

Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor

The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators. We found a novel class of non-covalent Keap1-Nrf2 PPI inhibitor that has a benzo[g]indole skeleton and an indole-3-hydroxamic acid moiety and that exhibits significant PPI inhibitory activity. Additionally, the benzo[g]indole-3-carbohydrazide derivatives were newly prepared. The benzo[g]indole derivatives showed a stronger Keap1-Nrf2 PPI inhibitory activity than Cpd16, a previously reported non-covalent PPI inhibitor. Moreover, most of the PPI inhibitors showed a high metabolic stability in a human microsome system with a low cytotoxicity against HepG2 cell lines, which suggests that novel benzo[g]indole-type Keap1-Nrf2 PPI inhibitors are expected to be biological tools or lead compounds for Nrf2 activators.     

Lignans and neolignans as lead compounds

Many lignans and neolignans have served as lead compounds for the development of new drugs. Perhaps the best known example is podophyllotoxin, an antimitotic compound that binds to tubulin. Etoposide and teniposide are derived from podophyllotoxin, but their antitumoural activity is due to inhibition of topoisomerase II. Combination of both pharmacophores has led to compounds with a dual mechanism of action, such as azatoxin. Dihydrobenzofuran neolignans, based on the natural lead 3,4-di-O-methylcedrusin, have also been investigated as potential antitumoural agents; the dimerisation product of caffeic acid methyl ester was the most active compound. Here too, he cytotoxic activity was due to inhibition of tubulin polymerisation. In addition, the same compounds showed antiangiogenic activity. Podophyllotoxin, as well as other types of lignans, such as dibenzylbutyrolactones related to arctigenin, dibenzocyclooctadiene-type lignans, and dibenzylbutanes, have been explored as leads for antiviral agents (also including HIV). Synthetic 8.O.4-neolignans have been evaluated for their antileishmanial and antifungal properties. Detailed study of the antifungal properties of the phenylpropanoid moieties has resulted in the design of highly active arylpropanoid derivatives. Other examples where lignans have been used as lead compounds include enzyme inhibitors of phosphodiesterase IV and V, and 5-lipoxygenase, and for the development of hypolipidemic and antirheumatic agents.     

Design,synthesis and potent cytotoxic activity of novel podophyllotoxin derivatives

Twenty new acyl thiourea derivatives of podophyllotoxin and 4′-demethylepipodophyllotoxin were prepared and screened for their cytotoxicity against four human tumor cell lines, A-549, DU-145, KB, and KBvin. With IC₅₀ values of 0.098–1.13 μM, compounds 13b, 13c, and 13o displayed much better cytotoxic activity than the control etoposide. Most importantly, 13b and 13o exhibited promising cytotoxicity against the drug resistant tumor cell line KBvin with IC₅₀ values of 0.098 and 0.13 μM, respectively, while etoposide lost activity completely. Structure–activity relationship (SAR) correlations of the new derivatives have been established. Compounds 13b and 13o merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.     

Synthesis of 4beta-amido and 4beta-sulphonamido analogues of podophyllotoxin as potential antitumour agents

The new 4beta-amido analogues of podophyllotoxin or 4'-O-demethylepipodophyllotoxin have been prepared either by the coupling of 4beta-amino podophyllotoxin or 4beta-amino-4'-O-demethyl epipodophyllotoxin with the corresponding acids in presence of DCC in dichloromethane or by treating the appropriate acid chloride or sulphonyl chloride in presence of Et(3)N. These 4beta-amido and 4beta-sulphonamido derivatives of podophyllotoxin have been evaluated for their cytotoxicity against six human cancer cell lines. Some of these analogues have shown promising anticancer activity.     

Synthesis of Novel (9S)‐Acyloxy Derivatives of Quinidine and Dihydroquinidine as Insecticidal Agents

Endeavor to discover biorational natural products‐based insecticides, two series (30) of novel (9S)‐acyloxy derivatives of quinidine and dihydroquinidine were prepared and assessed for their insecticidal activity against Mythimna separata in vivo by the leaf‐dipping method at 1 mg/mL. Among all the compounds, especially four derivatives exhibited the best insecticidal activity with final mortality rates of 71.4 %, 75.0 %, 71.4 %, and 75.0 %, respectively. Relatively speaking, 9‐hydroxy group is well tolerated, and the results showed that after modification of the hydroxy group with an acyloxy group, the insecticidal activity was significantly increased; the configuration at C8/9 position is important for insecticidal activity, and the (9S)‐configuration is optimal; modification of the out‐ring double bond is acceptable, and hydrogenation of the double bond enhances insecticidal activity. These preliminary results will pave the way for further modification of quinidine in the development of potential new insecticides.     

Synthesis,Biological Evaluation and Molecular Docking of Deferasirox and Substituted 1,2,4‐Triazole Derivatives as Novel Potent Urease Inhibitors: Proposing Repositioning Candidate

A series of new deferasirox derivatives were synthesized through the reaction of monosubstituted hydrazides with 2‐(2‐hydroxyphenyl)‐4H‐benzo[e][1,3]oxazin‐4‐one. For the first time, deferasirox and some of its derivatives were evaluated for their in vitro inhibitory activity against Jack bean urease. The potencies of the members of this class of compounds are higher than that of acetohydroxamic acid. Two compounds, bearing tetrazole and hydrazine derivatives (bioisoester of carboxylate group), represented the most potent urease inhibitory activity with IC₅₀ values of 1.268 and 3.254 μm , respectively. In silico docking studies were performed to delineate possible binding modes of the compounds with the enzyme, urease. Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its crucial amino acid residues, CME592 and His593. The overall results of urease inhibition have shown that these target compounds can be further optimized and developed as a lead skeleton for the discovery of novel urease inhibitors     

Synthesis and Anti-Oomycete Activity of 1-Sulfonyloxy/Acyloxydihydroeugenol Derivatives

Endeavor to discover biorational natural products-based fungicides, two series (26) of novel 1-sulfonyloxy/acyloxydihydroeugenol derivatives ( 3a – p and 5a – j ) were prepared and assessed for their fungicidal activity against P. capsici Leonian, in vitro. Results of fungicidal activity revealed that, among all compounds, especially compounds 3a , 5c , and 5e displayed the most potent anti-oomycete activity against P. capsici with EC₅₀ values of 69.33, 68.81, and 67.77 mg/L, respectively. Overall, the anti-oomycete activities of 1-acyloxydihydroeugenol derivatives ( 5a – j ) were higher than that of 1-sulfonyloxydihydroeugenol derivatives ( 3a – p ). It is proved that the introduction of the acyl group at hydroxy position of dihydroeugenol is more beneficial to improve its anti-oomycete activity than that of the sulfonyl group. These preliminary results will pave the way for further modification of dihydroeugenol in the development of potential new fungicides.     

Relaxant effects of selected sildenafil analogues in the rat aorta

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their relaxant effects in the rat aorta. Evaluation of prepared derivatives demonstrated that compound (8a) is probably a non-selective phosphodiesterase (PDE) inhibitor, as it induced aortic relaxation through endothelium-independent mechanism.     

Design and synthesis of 3-phenyltetrahydronaphthalenic derivatives as new selective MT2 melatoninergic ligands. Part II

Following our studies of the melatoninergic receptors, we have developed new tetrahydronaphthalenic derivatives of melatonin that have been tested as selective melatonin receptors ligands. Regarding the role of the phenyl substituent to obtain selective ligands, modulation of selectivity and activity have been achieved by modifications of the acyl group and substitutions on the phenyl ring. Ten of the seventeen evaluated derivatives have MT₂ receptor affinity similar to that of melatonin. Moreover, we have achieved remarkable MT₂ selectivity over MT₁ (selectivity >100) and have been able to further extend the RSA of the tetrahydrophthalenic series. However, the compounds presented here display partial agonist or antagonist behavior instead of full agonist.     

Design,Synthesis and Antiviral Activity of α-L-Arabinofuranosyl Derivatives of 2-Substituted-5,6-dichlorobenzimidazoles

Abstract

A number of 2-substituted-5,6-dichloro-l-(α-L-arabinofuranosyl)benzimidazoles have been prepared by condensation of 2-bromo-5,6-dichlorobenzimidazole or 2,5,6-trichlorobenzimidazole with tetra-O-acetyl-L-arabinofuranose. 2-Alkylamino derivatives were prepared by a substitution of the 2-chloro group with the appropriate amines. All target compounds were evaluated for activity against HCMV and HSV-1. The 2-chloro and 2-bromo derivatives showed moderate activity against HCMV at non-cytotoxic concentrations.     

Fluorinated indazoles as novel selective inhibitors of nitric oxide synthase (NOS): Synthesis and biological evaluation

In order to find new compounds with neuroprotective activity and NOS-I/NOS-II selectivity, we have designed, synthesized, and characterized 14 new NOS inhibitors with an indazole structure. The first group corresponds to 4,5,6,7-tetrahydroindazoles (4–8), the second to the N-methyl derivatives (9–12) of 7-nitro-1H-indazole (1) and 3-bromo-7-nitro-1H-indazole (2), and the latter to 4,5,6,7-tetrafluoroindazoles (13–17). Compound 13 (4,5,6,7-tetrafluoro-3-methyl-1H-indazole) inhibited NOS-I by 63% and NOS-II by 83%. Interestingly, compound 16 (4,5,6,7-tetrafluoro-3-perfluorophenyl-1H-indazole) inhibited NOS-II activity by 80%, but it did not affect to NOS-I activity. Structural comparison between these new indazoles further supports the importance of the aromatic indazole skeleton for NOS inhibition and indicate that bulky groups or N-methylation of 1 and 2 diminish their effect on NOS activity. The fluorination of the aromatic ring increased the inhibitory potency and NOS-II selectivity, suggesting that this is a promising strategy for NOS selective inhibitors.     

Synthesis and Cytotoxicity Assessment against Human Colorectal Cancer Cell Lines of Quaternary 8-Dichloromethyl Protoberberine Alkaloids

Twenty-two quaternary 8-dichloromethylprotoberberine alkaloids were synthesized from unmodified quaternary protoberberine alkaloids (QPAs) to improve their physical and chemical properties and to obtain selectively anticancer derivatives. The synthesized derivatives showed more appropriate octanol/water partition coefficients by up to values 3–4 compared to unmodified QPA substrates. In addition, these compounds exhibited significant antiproliferative activity against colorectal cancer cells and lower toxicity on normal cells, resulting in more significant selectivity indices than unmodified QPA compounds in vitro. The IC₅₀ values of antiproliferative activity of quaternary 8-dichloromethyl-pseudoberberine 4-chlorobenzenesulfonate and quaternary 8-dichloromethyl-pseudopalmatine methanesulfonate against colorectal cancer cells are 0.31 μM and 0.41 μM, respectively, significantly stronger than those of other compounds and positive control 5-fluorouracil. These findings suggest that 8-dichloromethylation can be used as one of the modification strategies to guide the structural modification and subsequent investigation of anticancer drugs for CRC based on QPAs.