Structure–activity studies on seco-pancratistatin analogs: Potent inhibitors of human cytochrome P450 3A4

Two total syntheses of fully functionalized seco-analogs of the anticancer compound pancratistatin are reported. Structure–activity relationship (SAR) studies identified potent and selective inhibitors of human cytochrome P450 3A4 (CYP3A4) and revealed several core pharmacophoric elements. These studies identify potential roadblocks and will guide the further development of a viable selective clinical pancratistatin derivative.     

Studies directed towards the refinement of the pancratistatin cytotoxic pharmacophore

Two deoxy-analogues of the anticancer/antiviral agent pancratistatin containing functionality complementary to the minimum structural pharmacophore were synthesized and subjected to anticancer screening. One of the analogues exhibited selective inhibition of certain tumor cell lines but was significantly less potent than the natural products. The minimum structural pharmacophore has now been refined from eight to three possible structures.     

Sesquiterpenoids from Chloranthus multistachys

An 8,9-seco-lindenane disesquiterpenoid, chloramultiol G, four eudesmane sesquiterpenoids, ent-(3R)-3-hydroxyatractylenolide III and multistalactones A–C, and four guaiane sesquiterpenoids, (1R,4S,5R,8S,10S)-zedoalactone A and multistalactones D–F, along with 14 known compounds, were isolated from whole plant tissues of Chloranthus multistachys. Their structures were established by extensive NMR experiments in conjunction with mass spectrometry. Except for chloramultiol G, the absolute stereochemistries of the other eight were confirmed by single-crystal X-ray crystallography and CD spectra. Nine compounds were tested for cytotoxicity against five human tumor cell lines and for antifungal activity against four microorganisms in vitro, but all were inactive.     

Synthesis and evaluation of vitamin D3 analogues with C-11 modifications as inhibitors of Hedgehog signaling

Previous structure-activity relationship studies have provided potent and selective analogues of vitamin D3 as inhibitors of the Hedgehog (Hh) signaling pathway. These analogues contain both modified A- and seco-B ring motifs, and have been evaluated for anticancer therapeutic potential. To continue our studies on this scaffold, a new series of compounds were synthesized to explore additional interactions and spatial constraints. These compounds incorporate functional groups of varying size and hydrophobicity at the C-11 position. While large hydrophobic moieties (9c–e) resulted in significant loss of Hh inhibition, smaller or more flexible moieties (9a, 11) maintain anti-Hh activity. These results call for additional and continued studies to identify the binding pocket to better understand these structure-activity relationships.     

Synthesis,anti-inflammatory,and antioxidant activities of 18β-glycyrrhetinic acid derivatives as chemical mediators and xanthine oxidase inhibitors

Twenty 18β-glycyrrhetic acid (18β-GA) derivatives 2–21 including 13 new 18β-GA derivatives were synthesized and evaluated as anti-inflammatory and antioxidant agents. Compounds 7 and 20 with a 3,4-seco-structure and compound 6 with a lactone moiety showed potent inhibitory effect on superoxide anion generation in rat neutrophils response to fMLP/CB and PMA, respectively. Compound 6 with a lactone moiety revealed stronger inhibitory effect on XO activity than those of compounds 13 and 14 with a 3,4-seco-struture. Compound 14, a 30-isoproylcarbamoyl seco-compound exhibited potent inhibitory effect on NO accumulation and iNOS protein expression while compounds 3, 10, 13, 15, 17, and 21 revealed potent inhibitory effect on tumor necrosis factor-α (TNF-α) formation in RAW 264.7 cells in response to lipopolysaccharide (LPS). The cleavage of ring A of 3 attenuated the inhibitory effect on TNF-α formation in RAW 264.7 cells in response to LPS except for 17. The present results suggested these compounds were potential to be served as anti-inflammatory and antioxidant agents.     

Eremophilane-type sesquiterpene lactones from Ligularia hodgsonii Hook

A dimeric eremophilane sesquiterpene lactone with a cyclobutane ring, biliguhodgsonolide (1) and an uncommon seco-sesquiterpene derivative, (4S,5S,6R,10R)-8,9-seco-12-hydroxyeremophil-7(11)-en-14,6;12,8-diolid-9-al (2), were isolated from the roots and rhizomes of Ligularia hodgsonii Hook. Their structures, including the absolute stereochemistry, were elucidated by spectroscopic data and CD analysis. The cyclobutane ring was confirmed by single-crystal X-ray diffraction.     

Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention

(2E,4E,6Z,8Z)-8-(3′,4′-Dihydro-1′(2H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.     

Synthesis,structure–activity relationships,and biological profiles of a dihydrobenzoxathiin class of histamine H3 receptor inverse agonists

A series of novel dihydrobenzoxathiin derivatives was synthesized and evaluated as potent human histamine H₃ receptor inverse agonists. After systematic modification of lead 1a, the potent and selective histamine H₃ inverse agonist 1-(3-{4-[(2S,3S)-8-methoxy-3-methyl-4,4-dioxido-2,3-dihydro-1,4-benzoxathiin-2-yl]phenoxy}propyl)pyrrolidine (5k) was identified. Compound 5k showed good pharmacokinetic profiles and brain penetrability in laboratory animals. After 3 mg/kg oral administration of 5k, significant elevation of brain histamine levels was observed in rats where the brain H₃ receptor was fully occupied.     

Decahydroisoquinoline derivatives as novel non-peptidic,potent and subtype-selective somatostatin sst3 receptor antagonists

Starting from non-peptidic sst₁-selective somatostatin receptor antagonists, first compounds with mixed sst₁/sst₃ affinity were identified by directed structural modifications. Systematic optimization of these initial leads afforded novel, enantiomerically pure, highly potent and sst₃-subtype selective somatostatin antagonists based on a (4S,4aS,8aR)-decahydroisoquinoline-4-carboxylic acid core moiety. These compounds can efficiently be synthesized and show promising PK properties in rodents.     

Flavans and other chemical constituents of Crinum biflorum (Amaryllidaceae)

The ethyl acetate extract from the whole plant of Crinum biflorum Rottb. Showed a moderate activity against Enterococcus faecalis. Its phytochemical investigation led to the isolation of a new flavan-3-ol derivative namely (2R,3R)-3-hydroxy-7-methoxy-3′,4′-methylenedioxyflavan, together with (2S)-7-hydroxy-3′,4′-methylenedioxyflavan, (2R,3R)-7-methoxy-flavan-3-ol, (2S)-7-hydroxy-3′,4′-dimethoxyflavan, 3′,7-dihydroxy-4′-methoxyflavan, 4′,7-dimethoxy-3′-hydroxyflavan, farrerol, β-sitosterol, β-sitosterol-3-O-β-D-glucopyranoside, oleanolic acid, kaempferol, pancratistatin, lupeol, aurantiamide acetate, Narciprimine and 2,3-dihydroxypropyl palmitate. Their structures were elucidated mainly by extensive spectroscopic analysis and comparison with published data. The absolute configuration of the new metabolite was determined by electronic circular dichroism (ECD) analysis and comparison of optical rotation. Some of the isolated compounds were tested for their antimicrobial activity but no inhibition was observed.     

Discovery of INCB10820/PF-4178903, a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist

We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate.     

Novel chemotactic For-Met-Leu-Phe-OMe (fMLF-OMe) analogues based on Met residue replacement by 4-amino-proline scaffold: Synthesis and bioactivity

cis-(2S,4S) 4-Amino-proline (cAmp) and trans-(2S,4R) 4-amino-proline (tAmp) residues, bearing N-For or N-Boc substituents at the two amino groups, have been incorporated into the potent chemotactic agent fMLF-OMe in place of the N-terminal native (S)-methionine to give the analogues 17a–19a and 17b–19b. The new ligands have been examined for their activity (chemotaxis, superoxide anion production and lysozyme release) on human neutrophils as agonists and antagonists. Compounds 19a and 19b, bearing two N-For groups at the proline scaffold, are active and selective chemoattractants. The ligand 18b, containing N-For at the 4-amino group of the N-Boc-tAmp residue, exhibits significant chemotactic antagonism. The influence of the different substitution at the N-terminal position of the new analogues is discussed.     

Discovery of phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one,an effective antithrombotic agent without associated bleeding and insulin resistance

Structure-based evolution of the original fragment leads resulted in the identification of 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, (S)-21, a potent, selective phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor with favourable in vivo antiplatelet effect. Despite its antiplatelet action, (S)-21 did not significantly increase bleeding time in dogs. Additionally, due to its enhanced selectivity over p110α, (S)-21 did not induce any insulin resistance in rats.     

2-Benzoylbenzofuran derivatives possessing piperazine linker as anticancer agents

A series of novel 2-benzoylbenzofuran derivatives possessing piperazine linker have been prepared, and their in vitro anticancer activity against a panel of human tumor cell lines by MTT assay were evaluated. The results demonstrated that tertiary amine derivatives exhibited better cytotoxic activity, and SAR study revealed that electron-donating substituents on the phenyl ring of the derivatization functionality contributed to potent anticancer activities. Among them, compounds 6, 9, 11, 18, 23 and 25 displayed both better anti-tumor activity and lower cytotoxic effect on human normal liver cell L02. Further apoptosis analysis showed that compound 18 significantly induced apoptosis in A549 cell, which was considered as the most potent anticancer agent.     

Design,synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of replacement of the 3-hydroxyphenyl group with pyridine or thiophene bioisosteres

The potent and selective KOR antagonist JDTic was derived from the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of pure opioid antagonists. In previous studies we reported that compounds that did not have a hydroxyl on the 3-hydroxyphenyl group and did not have methyl groups at the 3- and 4-position of the piperidine ring were still potent and selective KOR antagonists. In this study we report JDTic analogs 2, 3a–b, 4a–b, and 5, where the 3-hydroxyphenyl ring has been replaced by a 2-, 3-, or 4-pyridyl or 3-thienyl group and do not have the 3-methyl or 3,4-dimethyl groups, remain potent and selective KOR antagonists. Of these, (3R)-7-hydroxy-N-(1S)-2-methyl-[4-methyl-4-pyridine-3-yl-carboxamide (3b) had the best overall binding potency and selectivity in a [³⁵S]GTPγS functional assay, with a K_e = 0.18 nM at the KOR and 273- and 16,700-fold selectivity for the KOR relative to the MOR and DOR, respectively. Calculated physiochemical properties for 3b suggest that it will cross the blood–brain barrier.     

Antiplasmodial and cytotoxic activity of lanostane type triterpenoids isolated from Leplaea mayombensis

Leplaeric acid E 5, leplazarin 6a and 21-epileplazarin 6b, three new 3,4-seco-lanostane type triterpenes have been isolated from the stem bark of Leplaea mayombensis (Pellegr.) Staner along with fourteen known compounds from the fruits and roots. Leplaeric acid E, leplazarin and 21-epileplazarin, 15-α-hydroxy-3,4-seco-lanosta-4(28),8,24-triene-3,21-dioic acid, mayomlactones A and B, lanosta-7,24-dien-3-one, leplaeric acid A, B and C were screened in vitro for antiplasmodial activity against chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfINDO) strains of Plasmodium falciparum and for cytotoxicity against CAL-27, CaCo2, Skov-3, and HepG2 cells line. Three compounds including 15-α-hydroxy-3,4-seco-lanosta-4(28),8,24-triene-3,21-dioic acid (IC₅₀ 5.65–7.09 μM), lanosta-7,24-dien-3-one (IC₅₀ 7.18–9.07 μM), and leplaeric acid C (IC₅₀ 7.59–8.47 μM) were the most active against both strains of P. falciparum. All the compounds exhibited cytotoxicity against the three-cell lines with IC₅₀ ranging from 12.30 to 181.88 μM. These results confirm the usage of the medicinal plant L. mayombensis for the management of malaria and suggest that further lead optimization studies on potent compounds identified from this study could lead to the identification of potential of lead molecules as scaffold for new antimalarial drug discovery.     

A synthesis of 3-deoxydihydrolycoricidine: refinement of a structurally minimum pancratistatin pharmacophore

The synthesis of 3-deoxydihydrolycoricidine, a key element toward elucidation of the pancratistatin anticancer pharmacophore, is described. Biological evaluation of this compound showed it to be significantly less active against tumor cells than pancratistatin. In addition to those features previously identified, the requirement of a 2,3,4-triol functionalized ring-C is now definitely established as the minimum pharmacophoric element for potent anticancer activity.     

Structure–activity relationships of N-substituted ligands for the α7 nicotinic acetylcholine receptor

A series of α7 neuronal nicotinic acetylcholine receptor ligands were designed based on a structural combination of a potent, but non-selective ligand, epibatidine, with a selective lead structure, 2. Three series of compounds in which aryl moieties were attached via a linker to different positions on the core structure were studied. A potent and functionally efficacious analog, (3aR,6aS)-2-(6-phenylpyridazin-3-yl)-5-(pyridin-3-ylmethyl)octahydropyrrolo[3,4-c]pyrrole (3a), was identified.     

Discovery of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a): Histamine H3 receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity

A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H₃R antagonist. Compound R,S-4a was a potent H₃R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03–0.3 mg/kg po.