Camptothecin analogs with bulky, hydrophobic substituents at the 7-position via a Grignard reaction.


:By developing a new synthetic procedure for introduction of side chains onto the camptothecin ring system, we were able to achieve the preparation of a number of analogs bearing bulky, hydrophobic groups directly attached to the 7-position. These include 7-tert-butylcamptothecin, 7-benzylcamptothecin and the corresponding 10,11-methylenedioxycamptothecins. This method involves the reaction of an appropriate orthoaminobenzonitrile with various Grignard reagents to give the corresponding orthoaminoketones. Friedlander condensation of the latter with the key tricyclic ketone leads to 7-substituted camptothecin analogs. We report the activity of these compounds as topoisomerase I poisons and their ability to inhibit growth of selected tumor cell lines.


Bioorg Med Chem Lett


Manikumar G,Wadkins RM,Bearss D,Von Hoff DD,Wani MC,Wall ME




Has Abstract


2004-11-01 00:00:00














  • Discovery of (E)-1-amino-4-phenylbut-3-en-2-ol derivatives as novel neuraminidase inhibitors.

    abstract::Neuraminidase has been considered as an important target for designing agents against influenza viruses. In a discovery of anti-influenza agents with epigoitrin as the initial lead compound, a series of 1-amino-2-alkanols were synthesized and biologically evaluated. The in vitro evaluation indicated that (E)-1-amino-4...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lu C,Yin Y,Meng F,Dun Y,Pei K,Wang C,Xu X,Wu F

    更新日期:2018-06-15 00:00:00

  • DL-3-n-butylphthalide-Edaravone hybrids as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases with high antioxidant potency for Alzheimer's therapy.

    abstract::Considering the complex etiology of Alzheimer's disease (AD), multifunctional agents may be beneficial for the treatment of this disease. A series of DL-3-n-butylphthalide-Edaravone hybrids were designed, synthesized and evaluated as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases. Among them, co...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Qiang X,Li Y,Yang X,Luo L,Xu R,Zheng Y,Cao Z,Tan Z,Deng Y

    更新日期:2017-02-15 00:00:00

  • Synthesis and molecular modeling studies of 3-chloro-4-substituted-1-(8-hydroxy-quinolin-5-yl)-azetidin-2-ones as novel anti-filarial agents.

    abstract::A series of 3-chloro-4-substituted-1-(8-hydroxy-quinolin-5-yl)-azetidin-2-ones were synthesized and evaluated for their in vitro anti-filarial activity. To pre-assess the anti-filarial behavior of synthesized compounds (V(a-f)) on a structural basis, automated docking studies were carried out with Molecular Design Sui...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chhajed SS,Manisha P,Bastikar VA,Animeshchandra H,Ingle VN,Upasani CD,Wazalwar SS

    更新日期:2010-06-15 00:00:00

  • Optimization of 3-phenylpyrazolo[1,5-a]pyrimidines as potent corticotropin-releasing factor-1 antagonists with adequate lipophilicity and water solubility.

    abstract::In our efforts to identify potent CRF(1) antagonists with proper physicochemical properties, a series of 3-phenylpyrazolo[1,5-a]pyrimidines bearing polar groups, such as amino, hydroxyl, methoxy, sulfoxide, were designed and synthesized. Several positions of the core structure were identified, where a polar group was ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chen C,Wilcoxen KM,Huang CQ,McCarthy JR,Chen T,Grigoriadis DE

    更新日期:2004-07-16 00:00:00

  • The discovery and synthesis of highly potent, A2a receptor agonists.

    abstract::A series of N6,2-disubstituted adenosine analogues have been synthesized and their functional activity measured against A2a and A1 receptors. Examples of compounds with both a lipophilic N6-substituent and amino-functionalized 2-position were highly active at the A2a receptor on the human neutrophil. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Keeling SE,Albinson FD,Ayres BE,Butchers PR,Chambers CL,Cherry PC,Ellis F,Ewan GB,Gregson M,Knight J,Mills K,Ravenscroft P,Reynolds LH,Sanjar S,Sheehan MJ

    更新日期:2000-02-21 00:00:00

  • A fluorescent probe for GM1 gangliosidosis related β-galactosidase: N-(dansylamino)hexylaminocarbonylpentyl-1,5-dideoxy-1,5-imino-D-galactitol.

    abstract::N-(Dansylamino)hexylaminocarbonylpentyl-1,5-dideoxy-1,5-imino-D-galactitol, a strong competitive inhibitor of β-galactosidase, enhances residual β-galactosidase activities in fibroblasts and serves as lead en route to diagnostic compounds for tracking the fate of mutant β-gal as well as aberrant GM1 gangliosides by li...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Fröhlich RF,Fantur K,Furneaux RH,Paschke E,Stütz AE,Wicki J,Withers SG,Wrodnigg TM

    更新日期:2011-11-15 00:00:00

  • Marine sponge alkaloids as a source of anti-bacterial adjuvants.

    abstract::Novel approaches that do not rely upon developing microbicidal compounds are sorely needed to combat multidrug resistant (MDR) bacteria. The potential of marine secondary metabolites to serve as a source of non-traditional anti-bacterial agents is demonstrated by showing that pyrrole-imidazole alkaloids inhibit biofil...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Melander RJ,Liu HB,Stephens MD,Bewley CA,Melander C

    更新日期:2016-12-15 00:00:00

  • Novel nikkomycin analogues: inhibitors of the fungal cell wall biosynthesis enzyme chitin synthase.

    abstract::A series of novel nikkomycin analogue inhibitors of the chitin synthase of fungal cell wall was synthesized and evaluated for their inhibitory activities. Among them, the compound having a phenanthrene group at the terminal amino acid was found to possess strong anti-chitin synthase activity. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Obi K,Uda J,Iwase K,Sugimoto O,Ebisu H,Matsuda A

    更新日期:2000-07-03 00:00:00

  • Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity.

    abstract::Several recent reports have highlighted the feasibility of the use of penfluridol, a well-known antipsychotic agent, as a chemotherapeutic agent. In vivo experiments have confirmed the cytotoxic activity of penfluridol in triple-negative breast cancer model, lung cancer model, and further studies have been proposed to...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ashraf-Uz-Zaman M,Sajib MS,Cucullo L,Mikelis CM,German NA

    更新日期:2018-12-15 00:00:00

  • Microwave-assisted synthesis of novel 5-substituted benzylidene amino-2-butyl benzofuran-3-yl-4-methoxyphenyl methanones as antileishmanial and antioxidant agents.

    abstract::A series of 5-substitutedbenzylideneamino-2-butylbenzofuran-3-yl-4-methoxyphenyl methanones is synthesized and evaluated for antileishmanial and antioxidant activities. Compounds 4f (IC50 = 52.0 ± 0.09 µg/ml), 4h (IC50 = 56.0 ± 0.71 µg/ml) and 4l (IC50 = 59.3 ± 0.55 µg/ml) were shown significant antileishmanial when c...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Patil SR,Bollikonda S,Patil RH,Sangshetti JN,Bobade AS,Asrondkar A,Reddy PP,Shinde DB

    更新日期:2018-02-01 00:00:00

  • Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors.

    abstract::A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chen P,Norris D,Das J,Spergel SH,Wityak J,Leith L,Zhao R,Chen BC,Pitt S,Pang S,Shen DR,Zhang R,De Fex HF,Doweyko AM,McIntyre KW,Shuster DJ,Behnia K,Schieven GL,Barrish JC

    更新日期:2004-12-20 00:00:00

  • Synthesis and biological evaluation of ranitidine analogs as multiple-target-directed cognitive enhancers for the treatment of Alzheimer's disease.

    abstract::Using molecular modeling and rationally designed structural modifications, the multi-target structure-activity relationship for a series of ranitidine analogs has been investigated. Incorporation of a variety of isosteric groups indicated that appropriate aromatic moieties provide optimal interactions with the hydroph...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Gao J,Midde N,Zhu J,Terry AV,McInnes C,Chapman JM

    更新日期:2016-11-15 00:00:00

  • Molecular recognition of a DNA:RNA hybrid: sub-nanomolar binding by a neomycin-methidium conjugate.

    abstract::A novel neomycin-methidium conjugate was synthesized. The covalent linkage of the aminoglycoside to an intercalator, a derivative of ethidium bromide, results in a new conjugate capable of selective recognition of the DNA:RNA hybrid duplex. Spectroscopic methods: UV, CD, fluorescence, and calorimetric techniques: DSC ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Shaw NN,Xi H,Arya DP

    更新日期:2008-07-15 00:00:00

  • Antitumor platinum(II) complexes of N-cyclobutyl-1R,2R-diaminocyclohexane with dicarboxylates as leaving groups.

    abstract::Four platinum(II) complexes of N-cyclobutyl-1R,2R-diaminocyclohexane with different bidentate dicarboxylates (1 oxalate, 2 malonate, 3 1,1-cyclobutanedicarboxylate and 4 3-hydroxy-1,1-cyclobutanedicarboxylate) as leaving groups were synthesized and characterized by elemental analyses, IR and (1)HNMR spectra together w...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xu G,Zhao J,Gou S,Pang J

    更新日期:2015-01-15 00:00:00

  • Identification of a highly potent and selective CB2 agonist, RQ-00202730, for the treatment of irritable bowel syndrome.

    abstract::Herein we report the identification of a highly potent and selective CB2 agonist, RQ-00202730 (40), obtained by lead optimization of the benzimidazole scaffold. Compound 40 showed strong agonistic activity with an EC50 of 19nM and excellent selectivity (>1300-fold) over the CB1 receptor. Compound 40 displayed a dose d...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Iwata Y,Ando K,Taniguchi K,Koba N,Sugiura A,Sudo M

    更新日期:2015-01-15 00:00:00

  • Exploration of pyridine containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors.

    abstract::The diacylglycerol acyltransferase enzyme, DGAT1, presents itself as a potential target for obesity as this enzyme is dedicated to the final committed step in triglyceride biosynthesis. Biphenyl ureas, exemplified by compound 4, have been reported to be potent hDGAT1 inhibitors. We have synthesized and evaluated 2-pyr...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Motiwala H,Kandre S,Birar V,Kadam KS,Rodge A,Jadhav RD,Mahesh Kumar Reddy M,Brahma MK,Deshmukh NJ,Dixit A,Doshi L,Gupte A,Gangopadhyay AK,Vishwakarma RA,Srinivasan S,Sharma M,Nemmani KV,Sharma R

    更新日期:2011-10-01 00:00:00

  • SAR of a series of inhaled A(2A) agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data.

    abstract::COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Mantell SJ,Stephenson PT,Monaghan SM,Maw GN,Trevethick MA,Yeadon M,Walker DK,Selby MD,Batchelor DV,Rozze S,Chavaroche H,Lemaitre A,Wright KN,Whitlock L,Stuart EF,Wright PA,Macintyre F

    更新日期:2009-08-01 00:00:00

  • The search for novel TRPV1-antagonists: from carboxamides to benzimidazoles and indazolones.

    abstract::Based on a series of diaryl amides the corresponding inverse amides have been found to be potent TRPV1 receptor antagonists. Benzimidazole and indazolone derivatives prepared retained good potency in vitro and indazolone 4a was identified as a novel TRPV1 receptor antagonist suitable for evaluating orally in animal mo...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Fletcher SR,McIver E,Lewis S,Burkamp F,Leech C,Mason G,Boyce S,Morrison D,Richards G,Sutton K,Jones AB

    更新日期:2006-06-01 00:00:00

  • Ureas with histamine H3-antagonist receptor activity--a new scaffold discovered by lead-hopping from cinnamic acid amides.

    abstract::A group of tri and tetrasubstituted urea derivatives have been found to be hH(3)-antagonists. The most potent compounds were found in the class of (piperazine-1-yl)-(piperidine-1-yl)-methanones which in addition showed negligible hERG inhibition. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lau JF,Jeppesen CB,Rimvall K,Hohlweg R

    更新日期:2006-10-15 00:00:00

  • In vitro inhibition of human erythrocyte glutathione reductase by some new organic nitrates.

    abstract::Glutathione reductase (GR), is responsible for the existence of GSH molecule, a crucial antioxidant against oxidative stress reagents. The antimalarial activities of some redox active compounds are attributed to their inhibition of antioxidant flavoenzyme glutathione reductase, and inhibitors are therefore expected to...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Sentürk M,Talaz O,Ekinci D,Cavdar H,Küfrevioğlu OI

    更新日期:2009-07-01 00:00:00

  • Pyrrolnitrin and related pyrroles endowed with antibacterial activities against Mycobacterium tuberculosis.

    abstract::During development of nitroheterocycles with potential antimycobacterial activities we have tested against Mycobacterium tuberculosis a number of pyrroles strictly related to pyrrolnitrin, an antifungal antibiotic isolated from Streptomyces pyrrocinia. Some of the tested arylpyrrole derivatives and pyrrolnitrin have s...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Di Santo R,Costi R,Artico M,Massa S,Lampis G,Deidda D,Pompei R

    更新日期:1998-10-20 00:00:00

  • A bivalent ligand (KMN-21) antagonist for mu/kappa heterodimeric opioid receptors.

    abstract::In an effort to develop antagonists for kappa-mu opioid receptor heterodimers, a series of bivalent ligands 3-6 containing kappa- and mu-antagonist pharmacophores were designed and synthesized. Evaluation of the series in HEK-293 cells revealed 4 (KMN-21) to selectively antagonize the activation of kappa-mu heterodime...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zhang S,Yekkirala A,Tang Y,Portoghese PS

    更新日期:2009-12-15 00:00:00

  • Synthesis and evaluation of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-aminopropanamide as human cannabinoid-1 receptor (CB1R) inverse agonists.

    abstract::Obesity is a chronic medical condition that is affecting large population throughout the world. CB1 as a target for treatment of obesity has been under intensive studies. Taranabant was discovered and then developed by Merck as the 1st generation CB1R inverse agonist. Reported here is part of our effort on the 2nd gen...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Du W,Jewell JP,Lin LS,Colandrea VJ,Xiao JC,Lao J,Shen CP,Bateman TJ,Reddy VB,Ha SN,Shah SK,Fong TM,Hale JJ,Hagmann WK

    更新日期:2009-09-01 00:00:00

  • Himbacine derived thrombin receptor (PAR-1) antagonists: SAR of the pyridine ring.

    abstract::The structure-activity relationship (SAR) of the vinyl pyridine region of himbacine derived thrombin receptor (PAR-1) antagonists is described. A 2-vinylpyridyl ring substituted with an aryl or a heteroaryl group at the 5-position showed the best overall PAR-1 affinity and pharmacokinetic properties. One of the newly ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xia Y,Chackalamannil S,Clasby M,Doller D,Eagen K,Greenlee WJ,Tsai H,Agans-Fantuzzi J,Ahn HS,Boykow GC,Hsieh Y,Lunn CA,Chintala M

    更新日期:2007-08-15 00:00:00

  • A novel approach toward bacteriochlorophylls-e and f.

    abstract::Methyl bacteriopheophorbide-f was prepared from methyl bacteriopheophorbide-d with retention of the 3(1)-chirality. The transformation of the methyl to the formyl group at the 7-position of the chlorin moiety will provide an alternative route for the synthesis of bacteriochlorophylls-e and f. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tamiaki H,Omoda M,Kubo M

    更新日期:1999-06-21 00:00:00

  • Affibody-displaying bio-nanocapsules effective in EGFR, typical biomarker, expressed in various cancer cells.

    abstract::The expression of epidermal growth factor receptor (EGFR) across a wide range of tumor cells has attracted attention for use as a tumor marker in drug delivery systems. Therefore, binding molecules with the ability to target EGFR have been developed. Among them, we focused on affibodies that are binding proteins deriv...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Nishimura Y,Ezawa R,Ishii J,Ogino C,Kondo A

    更新日期:2017-01-15 00:00:00

  • Potent hFPRL1 (ALXR) agonists as potential anti-inflammatory agents.

    abstract::We report the discovery of potent agonists for the human formyl-peptide-like 1 receptor (hFPRL1). These compounds did not act at a closely related receptor denoted human formyl peptide receptor (hFPR) up to 10 microM concentration. Recent studies have indicated that agonizing this receptor may promote resolution of in...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bürli RW,Xu H,Zou X,Muller K,Golden J,Frohn M,Adlam M,Plant MH,Wong M,McElvain M,Regal K,Viswanadhan VN,Tagari P,Hungate R

    更新日期:2006-07-15 00:00:00

  • SAR of N-phenyl piperidine based oral integrin alpha5beta1 antagonists.

    abstract::Recently, a new class of selective integrin alpha5beta1inhibitors consisting of a heterocyclic based scaffold was published. Herein the SAR and pharmacokinetic profiles of N-phenyl piperidine derivatives are described. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zischinsky G,Osterkamp F,Vossmeyer D,Zahn G,Scharn D,Zwintscher A,Stragies R

    更新日期:2010-01-01 00:00:00

  • Synthesis of bivalent lactosides and their activity as sensors for differences between lectins in inter- and intrafamily comparisons.

    abstract::The synthesis of nine bivalent lactosides (based on ditriazoles, diamides, a glycocyclophane and an acyclic analogue of the glycocyclophane) and one monovalent lactosyl triazole facilitated the assessment of the sensitivity of plant/animal lectins to this type of ligand display. The inhibitory potency of the compounds...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: André S,Jarikote DV,Yan D,Vincenz L,Wang GN,Kaltner H,Murphy PV,Gabius HJ

    更新日期:2012-01-01 00:00:00

  • Synthesis and biological activity of 4-substituted benzoxazolone derivatives as a new class of sEH inhibitors with high anti-inflammatory activity in vivo.

    abstract::A series of novel 4-substituted benzoxazolone derivatives was synthesized, characterized and evaluated as human soluble epoxide hydrolase (sEH) inhibitors and anti-inflammatory agents. Some compounds showed moderate sEH inhibitory activities in vitro, and two novel compounds, 3g and 4j, exhibited the highest activitie...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tang L,Ma WH,Ma YL,Ban SR,Feng XE,Li QS

    更新日期:2013-04-15 00:00:00