Total Synthesis and Biological Evaluation of (+)‐Neopeltolide and Its Analogues

The stereocontrolled total synthesis of the originally proposed ( 1 ) and correct ( 2 ) structures of (+)‐neopeltolide, a novel marine macrolide natural product with highly potent antiproliferative activity against several cancer cell lines as well as potent antifungal activity, has been achieved by exploiting a newly developed Suzuki–Miyaura coupling/ring‐closing metathesis strategy. Alkylborate 44 , which was generated in situ from iodide 34 , was coupled with enol phosphate 8 by a Suzuki–Miyaura coupling. Ring‐closing metathesis of the derived diene 45 followed by stereoselective hydrogenation afforded tetrahydropyran 47 as a single stereoisomer in high overall yield from 34 . Our convergent strategy enabled us to construct the 14‐membered macrolactone core structure of 2 in a rapid and efficient manner. Total synthesis and biological evaluation of synthetic intermediates and designed synthetic analogues, performed to establish the structure–activity relationships of 2 , led to the discovery of a structurally simple yet potent cytotoxic analogue, 9‐demethylneopeltolide ( 54 ).     

Synthesis,Antiproliferative, and c‐Src Kinase Inhibitory Activities of 4‐Oxo‐4H‐1‐benzopyran Derivatives

A new class of 4‐oxo‐4H‐1‐benzopyran derivatives were synthesized and their antiproliferative activity examined against a panel of three human cancer cell lines, that is, breast carcinoma (MDA‐MB‐468), ovarian adenocarcinoma (SK‐OV‐3), and colorectal adenocarcinoma (HT‐29). Two compounds, that is, 3‐hexyl‐7,8‐dihydroxy‐4‐oxo‐4H‐1‐benzopyran and (E)‐ethyl 3‐(7‐methoxy‐4‐oxo‐4H‐1‐benzopyran‐3‐yl)acrylate were found to be potent against all three cancer cell lines studied at 50 μM concentration. Also, the inhibitory potency of the compounds was evaluated against active Src kinase. A few of these compounds exhibited modest Src kinase inhibitory activity (IC₅₀ = 52–57 μM). Structure‐activity relationship studies with respect to the nature and position of substituents on the lead compounds could be further exploited for the design and development of more potent antiproliferative agents and/or Src kinase inhibitors.     

FeCl3‐Catalyzed Ring‐Closing Carbonyl–Olefin Metathesis

Exploiting catalytic carbonyl–olefin metathesis is an ongoing challenge in organic synthesis. Reported herein is an FeCl₃‐catalyzed ring‐closing carbonyl–olefin metathesis. The protocol allows access to a range of carbo‐/heterocyclic alkenes with good efficiency and excellent trans diastereoselectivity. The methodology presents one of the rare examples of catalytic ring‐closing carbonyl–olefin metathesis. This process is proposed to take place by FeCl₃‐catalyzed oxetane formation followed by retro‐ring‐opening to deliver metathesis products.     

Synthesis and Antiproliferative Evaluation of 2′‐Arenesulfonyloxy‐5‐benzylidene‐thiazolidine‐2,4‐diones

A series of 2′‐arenesulfonyloxy‐5‐benzylidene‐thiazolidine‐2,4‐diones (TZDs) were synthesized and examined for their antiproliferative effects on a panel of carcinoma cell lines. Our results indicated that initial synthesis of 5‐[2′‐hydroxybenzylidene]‐2,4‐thiazolidinone (9) by Knoevenagel condensation followed by nucleophilic substitution with arylsulfonyl chlorides exhibited superior efficiency to the alternative synthetic route. Among tested compounds, only 8c and 8e showed significant antiproliferative activity against PC‐3 and BT474 cells with GI₅₀ values of 8.4 and 20.6 μM, respectively. SKHep cells displayed interesting structure‐activity relationships in response to TZD derivatives treatment. Alkyl group‐substituted TZD analogs such as 8a (4‐Me, GI₅₀, 9.4 μM) and 8k (4‐iso‐propyl, GI₅₀, 9.8 μM) revealed better antiproliferative activity than those with bulkier alkyl groups. On the other hand, halogen‐substituted TZD analogs 8c, 8h, and 8i showed better antiproliferative activity against H460 cell line. Together, the new synthesized TZD derivatives 8a , 8b , 8c , 8d , 8e , 8f , 8g , 8h , 8i , 8j , 8k , 8l , 8m , 8n , 8o , 8p exhibited appreciable antiproliferative activity worth for further study.     

Total Synthesis of (+)‐trans‐Trikentrin A

Several syntheses have already been reported for cis‐trikentrins and herbindoles, which are indole alkaloids unsubstituted at the C2 and C3 positions that bear a trans‐1,3‐dimethylcyclopentyl unit. Herein, we describe the first asymmetric and stereoselective synthesis of the more challenging trans‐trikentrin A as its naturally occurring isomer. Different approaches were investigated and the strategy of choice was a combination of an enzymatic kinetic resolution and a thallium(III)‐mediated ring contraction. The antiproliferative activities of the natural product and related intermediates have been tested against human tumor cell lines, leading to the discovery of new compounds with potent antitumor activity.     

Total Synthesis of (−)‐Enigmazole A

Total synthesis of (?)‐enigmazole A, a marine macrolide natural product with cytotoxic activity, has been accomplished. The tetrahydropyran moiety was constructed by means of a domino olefin cross‐metathesis/intramolecular oxa‐Michael addition of a δ‐hydroxy olefin. After coupling of advanced intermediates, the macrocycle was formed through gold‐catalyzed rearrangement of a propargylic benzoate, followed by ring‐closing metathesis of the resultant α,β‐unsaturated ketone.     

Total synthesis and biological assessment of (-)-exiguolide and analogues

We describe herein an enantioselective total synthesis of (-)-exiguolide, the natural enantiomer. The methylene bis(tetrahydropyran) substructure was efficiently synthesized by exploiting olefin cross-metathesis for the assembly of readily available acyclic segments and intramolecular oxa-conjugate cyclization and reductive etherification for the formation of the tetrahydropyran rings. The 20-membered macrocyclic framework was constructed in an efficient manner by means of Julia-Kocienski coupling and Yamaguchi macrolactonization. Finally, the (E,Z,E)-triene side chain was introduced stereoselectively via Suzuki-Miyaura coupling to complete the total synthesis. Assessment of the growth inhibitory activity of synthetic (-)-exiguolide against a panel of human cancer cell lines elucidated for the first time that this natural product is an effective antiproliferative agent against the NCI-H460 human lung large cell carcinoma and the A549 human lung adenocarcinoma cell lines. Moreover, we have investigated structure-activity relationships of (-)-exiguolide, which elucidated that the C5-methoxycarbonylmethylidene group and the length of the side chain are important for the potent activity.     

Novel 5‐Methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐ 3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole Derivatives: Synthesis and Anticancer Activity

Eleven novel 5‐methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole derivatives were synthesized and characterized by elemental analysis, ESI‐MS, ¹H NMR and ¹³C NMR. All of the compounds have been screened for their antiproliferative activities against PC‐3 cell (human prostate cancer) and A431 cell (human epidermoid carcinoma cancer) lines in vitro. The results revealed that compounds 4g , 4j and 4k exhibited the strong inhibitory activities against the PC‐3 cell lines (with IC₅₀ values of 2.8±0.11, 3.1±0.10 and 3.0±0.06 μg/mL, respectively).     

Synthesis and Cytotoxicity of 1,4‐Dihydropyridines and an Unexpected 1,3‐Oxazin‐6‐one

Eight heterocycles have been prepared in a one‐pot reaction manner based on the Hantzsch dihydropyridine synthesis. The synthesis afforded seven dihydropyridines (DHP) and one unexpected 1,3‐oxazin‐6‐one. Their structures were confirmed based on NMR spectroscopy and mass spectrometry. The obtained products have been evaluated for their cytotoxicity against eight cancer cell lines and one normal cell line. Two halogenated DHPs ( 7 and 8 ) displayed cytotoxicity toward all the nine tested cancer cell lines with IC₅₀ values from 4.10 to 58.90 μm, while others showed selective activities. DHPs ( 7 and 8 ) bearing a Me group at C(2) and C(6) as well as a halogenated substituent at C(4′) were more antiproliferative than the others.     

Unified Asymmetric Total Syntheses of (−)‐Alotaketals A–D and (−)‐Phorbaketal A

The novel tricyclic spiroketal alotane‐type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (−)‐alotaketals A–D and (−)‐phorbaketal A were accomplished [29–31 steps from (−)‐malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy δ‐keto‐alcohols to forge the common tricyclic spiroketal intermediate, 2) a late‐stage allylic C−H oxidation, and 3) olefin cross‐metathesis to install the different side chains.     

Probing o‐Diphenylphosphanyl Benzoate (o‐DPPB)‐Directed CC Bond Formation: Total Synthesis of Dictyostatin

Herein, we report a robust total synthesis of dictyostatin. This polyketide natural product has attracted much attention because of its impressive antiproliferative activity against several human cancer‐cell lines. We accomplished its synthesis in a highly convergent manner from three fragments of equal complexity, which were prepared on multigram scale. The southern and northwestern subunits were constructed through application of our o‐DPPB‐directed hydroformylation and allylic substitution methodology, respectively. These methods generated the C6 and C14 stereocenters of dictyostatin with good diastereoselectivities and simultaneously allowed further elaboration of the fragments by Wittig olefination and Sharpless asymmetric epoxidation, respectively. The compelling performance of the hydroformylation and allylic substitution with regard to practicability, selectivity, and scale underline their value for the construction of propionate motifs.     

Synthesis and Biological Activity of 7,8,9‐Trideoxy‐ and 7R DesTHP‐Peloruside A

The stereoselective syntheses of 7,8,9‐trideoxypeloruside A ( 4 ) and a monocyclic peloruside A analogue lacking the entire tetrahydropyran moiety ( 3 ) are described. The syntheses proceeded through the PMB‐ether of an ω‐hydroxy β‐keto aldehyde as a common intermediate which was elaborated into a pair of diastereomeric 1,3‐syn and ‐anti diols by stereoselective Duthaler–Hafner allylations and subsequent 1,3‐syn or anti reduction. One of these isomers was further converted into a tetrahydropyran derivative in a high‐yielding Prins reaction, to provide the precursor for bicyclic analogue 4 . Downstream steps for both syntheses included the substrate‐controlled addition of a vinyl lithium intermediate to an aldehyde, thus connecting the peloruside side chain to C15 (C13) of the macrocyclic core structure in a fully stereoselective fashion. In the case of monocyclic 3 macrocyclization was based on ring‐closing olefin metathesis (RCM), while bicyclic 4 was cyclized through Yamaguchi‐type macrolactonization. The macrolactonization step was surprisingly difficult and was accompanied by extensive cyclic dimer formation. Peloruside A analogues 3 and 4 inhibited the proliferation of human cancer cell lines in vitro with micromolar and sub‐micromolar IC₅₀ values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for nM biological activity.     

Design,Synthesis, and Evaluation of Tetraethylene Glycol‐Tethered Isatin–1,2,3‐Triazole–Coumarin Hybrids as Novel Anticancer Agents

We report herein the design and synthesis of a series of novel tetraethylene glycol‐tethered isatin–1,2,3‐triazole–coumarin hybrids and evaluate their in vitro antitumor activities against seven common human cancer cell lines including drug‐resistant cell line. Results revealed that all the synthesized hybrids showed weak to moderate activities against the tested seven cancer cell lines. The structure–activity relationship was also discussed, and the enriched structure–activity relationship may pave the way for further rationale design of this kind of hybrids.     

(Benzyl isocyanide)gold(I) pyrimidine‐2‐thiolate complex: Synthesis and biological activity

The reaction of [(Me₂S)AuCl] with an equimolar amount of benzyl isocyanide (PhCH₂NC) ligand led to the formation of complex [(PhCH₂NC)AuCl] ( 1 ). The solid‐state structure of 1 was determined using the X‐ray diffraction method. Through a salt metathesis reaction, the chloride ligand in 1 was replaced by pyrimidine‐2‐thiolate (SpyN^?) to afford the complex [(PhCH₂NC)Au(η¹‐S‐Spy)] ( 2 ), which was characterized spectroscopically. The cytotoxic activities of 1 and 2 were evaluated against three human cancer cell lines: ovarian carcinoma (SKOV3), lung carcinoma (A549) and breast carcinoma (MCF‐7). Complex 2 showed higher cytotoxicity than cisplatin against SKOV3 and MCF‐7 cancer cell lines. It showed a strong anti‐proliferative activity with IC₅₀ of 7.80, 6.26 and 6.14 μM, compared with that measured for cisplatin which was 7.62, 12.36 and 11.47 μM, against A549, SKOV3 and MCF‐7 cell lines, respectively. The induction of cellular apoptosis by 2 was also studied on MCF‐7 cell line. Our results indicated that 2 could induce apoptosis in cancerous cells in a dose‐dependent manner.     

Synthesis and biological evaluations of mono‐ and bis‐ferrocene uracil derivatives

Mono‐ ( 3a – 3e and 4a – 4e ) and bis‐ferrocene ( 5a – 5e and 6a – 6e ) conjugated 5‐substituted uracil derivatives that are bridged by 1,2,3‐triazole linker were synthesized. The impact of ferrocene unit and spacer between ferrocene and triazole on radical scavenging potency was observed. Bis‐ferrocenyl uracil derivatives exhibited better antiproliferative activities than their mono‐ferrocenyl analogs. Bis‐ferrocenyl methyl‐ ( 5b ) and halogen‐substituted ( 5e , 6c , and 6d ) uracil derivatives showed pronounced and selective cytostatic activities on colon adenocarcinoma (CaCo‐2) and Burkitt lymphoma (Raji) cells, with higher potency and selectivity than the reference drug 5‐fluorouracil. Generation of reactive oxygen species (ROS) in CaCo‐2 and Raji cells when treated with compounds 5b , 5e , and 6d was observed. Bis‐ferrocenyl 5‐chlorouracil 6c induced significant disruption in mitochondrial membrane potential that is accompanied by activation of apoptosis in CaCo‐2, Raji, and acute lymphoblastic leukemia (CCRF‐CEM) cells, while 6d caused mitochondrial dysfunction and apoptosis induction in CaCo‐2 and Raji cells. Potent antiproliferative activity of 6c and 6d could be associated with mitochondrial membrane potential disruption accompanied by apoptosis induction. Our findings highlighted 6c and 6d with potent and selective antiproliferative activity on CaCo‐2, Raji, and CCRF‐CEM cells that may be associated with targeting cancer cell mitochondria, as a molecular target.     

Synthesis and Antiproliferative Activity of 6‐Ferrocenyl‐3‐Substituted 7H‐1,2,4‐Triazolo[3, 4‐b]‐1,3,4‐Thiadiazines

Five new 6‐ferrocenyl‐3‐substituted 7H‐1,2,4‐triazolo[3, 4‐b]‐1,3,4‐thiadiazines ( 3a‐e ) have been synthesized and characterized on the basis of elemental analyses and spectral data. The antiproliferative activities were examined in two human cell lines (BJ and HT 1080) with the acid phosphatase assay. The results showed that all compounds could reduce cell viability. The significant difference between the two cell lines was that fibrosarcoma HT 1080 cells could indeed be more susceptible to the compounds than the normal fibroblast BJ cells.     

Sulfonated N‐heterocyclic carbine‐silver (I) complexes: Synthesis,characterisation and biological evaluation

The synthesis, characterisation and biological activity of water‐soluble Ag(I)‐NHC complexes, general formula Na[(NHC)AgCl] where NHC is a sulfonated and sterically hindered N‐heterocyclic carbene, is reported. The Ag‐NHC complexes (2a–e) were synthesised by reacting the corresponding sulfonated NHC ligands with Ag₂O in the presence of NaCl or NaBr in methanol/water (1:1) solution. Synthesised silver (I)‐N‐heterocyclic carbene complexes have been characterised by NMR, micro‐analysis and HRMS spectroscopic methods. The IC₅₀ values of these complexes were determined by a proliferation BrdU enzyme‐linked immunosorbent assay (ELISA) against HeLa (human cervix carcinoma), HT29 (human adenocarcinoma) and L929 (mouse fibroblast) cell lines. These complexes have been highlighted as promising and original platforms for building new types of metalodrug. All new water‐soluble Ag(I) complexes demonstrated remarkable cytotoxic activity against HeLa, HT29 and L929 cell lines.     

A new biologically active molecular scaffold: crystal structure of 7‐(3‐hydroxyphenyl)‐4‐methyl‐2H‐[1,2,4]triazolo[3,2‐c][1,2,4]triazole and selective antiproliferative activity of three isomeric triazolo–triazoles

A study of three isomeric compounds containing a phenolic moiety attached to the nitrogen‐rich triazolo–triazole bicycle is presented. In the three isomers, the phenolic OH group is in the ortho, meta and para positions. The crystal structure analysis of the meta isomer (C₁₀H₉N₅O) shows that the 2H‐tautomer is present in the crystal and that the molecule adopts a substantially planar geometry. However, the conformation found in the crystal is different compared to the monoprotonated cation of the same compound previously investigated in several salts. The packing of the meta isomer is driven by the formation of strong hydrogen bonds and shows the formation of infinite planar ribbons, parallel to a, formed around 2₁ crystallographic axes. The three isomers were tested against some cancer cell lines and also against normal cell lines. The ortho isomer shows a weak antiproliferative activity, the meta isomer shows significant antiproliferative activity against some cancer lines and no activity against healthy cell lines, and the para isomer is active against all the tested cell lines.     

Total Synthesis of (+)‐Cryptocaryalactone and of a Diastereoisomer of (+)‐Strictifolione via Ring‐Closing Metathesis (RCM) and Olefin Cross‐Metathesis (CM)

Ring‐closing metathesis (RCM) and olefin cross‐metathesis (CM) reactions were used as the key steps for the synthesis of (+)‐cryptocaryalactone ( 1 ) and the first synthesis of the diastereoisomer 3 of (+)‐strictifolione, starting from the commercially available L ‐malic acid (=(2S)‐2‐hydroxybutanedioic acid).     

Synthesis,Anticancer Evaluation,and Molecular Docking Studies of Novel (4‐Hydroxy‐2‐Thioxo‐3,4‐Dihydro‐2H‐[1,3]Thiazin‐6‐Yl)‐Chromen‐2‐Ones via a Multicomponent Approach

A series of coumarin‐substituted 1,3‐thiazine‐2‐thione derivatives ( 4a–m ) were synthesized via the multicomponent reaction of 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehyde ( 1 ) carbon disulfide ( 2 ), and various primary amines ( 3 ), in presence of triethylamine and acetonitrile under stirring with good yields. The structures of all the synthesized compounds were characterized by analytical and spectral studies. Further, the synthesized compounds were screened for their in vitro antiproliferative activities against different cancer cell lines (A549, MDA‐MB‐231, MCF7, HeLa, and B16F10). Studies on the molecular interactions to recognize the hypothetical binding motif of the title compounds with the target Hsp 100 were carried out employing the Schrodinger software. Compounds 4a , 4c and 4m showed activity against all the five cell lines compared with the reference drug, and 4a exhibited the least IC₅₀ concentration of 7.56 ± 1.07 μg/mL against MCF7. This in vitro anticancer result was supported by in silico docking and in silico ADME (absorption, distribution, metabolism, and excretion) studies as well.