Novel N-mustard-benzimidazoles/benzothiazoles Hybrids, Synthesis and Anticancer Evaluation.

Background: Bendamustine, an N-mustard-benzoimidazole hybrid conjugate, was recently approved for the treatment of chronic lymphocytic leukemia. However, the short half-life of bendamustine may limit its clinical applications.

Objective: The purpose of this study is to design and synthesize compounds with a more favorable pharmacokinetic profile.

Design and Synthesis of 1,4-dihydropyridine Derivatives as Anti-cancer Agent.

Aims: A series of 1,4-dihydropyridine based compounds bearing benzylpyridinium moiety have been designed and evaluated for in vitro anticancer activity against glioblastoma U87MG, lung cancer A549 and colorectal adenocarcinoma Caco-2 cell lines using the MTT assay.

Method: Among these compounds, 7b, 7d, 7e, and 7f exhibited potent anticancer activity against the cell lines tested. The cytotoxicity of the synthesized derivatives was compared to standard drugs (carboplatin, gemcitabine, and daunorubicin).

Derivatives of 6-cinnamamido-quinoline-4-carboxamide impair lysosome function and induce apoptosis.

Autophagy is a lysosomal degradative process that protects cancer cells from multiple types of stress. In this study, we synthesized a series of derivatives of 6-cinnamamido-quinoline-4-carboxamide (CiQ), and investigated their effects on the proliferation and autophagy of cancer cells in vitro. These derivatives effectively inhibited the proliferation of a broad spectrum of cancer cell lines.

Repairing of N-mustard derivative BO-1055 induced DNA damage requires NER, HR, and MGMT-dependent DNA repair mechanisms.

Alkylating agents are frequently used as first-line chemotherapeutics for various newly diagnosed cancers. Disruption of genome integrity by such agents can lead to cell lethality if DNA lesions are not removed. Several DNA repair mechanisms participate in the recovery of mono- or bi-functional DNA alkylation.

The synthesis and biological evaluation of new DNA-directed alkylating agents, phenyl N-mustard-4-anilinoquinoline conjugates containing a urea linker.

We synthesized a series of phenyl N-mustard-4-anilinoquinoline conjugates to study their antitumorigenic effects. These agents were prepared by the condensation of 4-[N,N-bis(2-chloroethyl)amino]phenyl isocyanate with 6-amino-4-methylamino or 4-anilinoquinolines. The structure-activity relationship (SAR) studies revealed that the C2-methylquinoline derivatives (18a-o) were generally more cytotoxic than the C2-phenylquinoline conjugates (23a-d) in inhibiting the cell growth of various human tumor cell lines in vitro.

PI3K Inhibition Augments the Therapeutic Efficacy of a 3a-aza-Cyclopenta[α]indene Derivative in Lung Cancer Cells.

The synergistic targeting of DNA damage and DNA repair is a promising strategy for the development of new chemotherapeutic agents for human lung cancer. The DNA interstrand cross-linking agent BO-1509, a derivative of 3a-aza-cyclopenta[α]indene, was synthesized and combined with the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 to treat human lung cancer cells. Our results showed that the BO-1509 and LY294002 combination synergistically killed lung cancer cells in culture and also suppressed the growth of lung cancer xenografts in mice, including those derived from gefitinib-resistant cells.

Inhibition of autophagy enhances DNA damage-induced apoptosis by disrupting CHK1-dependent S phase arrest.

DNA damage has been shown to induce autophagy, but the role of autophagy in the DNA damage response and cell fate is not fully understood. BO-1012, a bifunctional alkylating derivative of 3a-aza-cyclopenta[a]indene, is a potent DNA interstrand cross-linking agent with anticancer activity. In this study, BO-1012 was found to reduce DNA synthesis, inhibit S phase progression, and induce phosphorylation of histone H2AX on serine 139 (γH2AX) exclusively in S phase cells.

Design and synthesis of potent antitumor water-soluble phenyl N-mustard-benzenealkylamide conjugates via a bioisostere approach.

A series of new, water-soluble phenyl N-mustard-benzenealkylamide conjugates containing hydrophilic ω-dialkylaminoalkylamide or ω-cyclic aminoalkylamide moieties were synthesized via a bioisostere approach. These compounds have a broad spectrum of antitumor activity against a panel of human tumor cell lines. Of these derivatives, compound 18b effectively suppressed the growth of colon cancer (HCT-116), prostate cancer (PC3), and lung cancer (H460) xenografts.

The development of bis(hydroxymethyl)pyrrole analogs as bifunctional DNA cross-linking agents and their chemotherapeutic potential.

Bifunctional DNA cross-linking agents are widely used as chemotherapeutic agents in clinics. The advance in the development of these agents as potential antitumor agents has generated various types of bis(hydroxymethyl)pyrrole analogs. In order to develop highly effective anticancer agents, it is necessary to understand the chemophysical properties, structure-activity relationships, therapeutic potency, toxicity/safety, and pharmacokinetics of these DNA cross-linking agents.

Novel antitumor indolizino[6,7-b]indoles with multiple modes of action: DNA cross-linking and topoisomerase I and II inhibition.

A series of bis(hydroxymethyl)indolizino[6,7-b]indoles and their bis(alkylcarbamates) were synthesized for antitumor studies. These agents were designed as hybrid molecules of β-carboline (topoisomerase inhibition moiety) and bis(hydroxymethyl)pyrrole (DNA cross-linking moiety). The preliminary antitumor studies indicated that these agents exhibited significant cytotoxicity against a variety of human tumor cells in vitro.

Determination of tissue distribution of potent antitumor agent ureidomustin (BO-1055) by HPLC and its pharmacokinetic application in rats.

Ureidomustin hydrochloride (BO-1055) was designed as a water-soluble nitrogen-mustard, which exhibited potent anticancer activity and was selected as a candidate for preclinical studies. However, up to date, there is rarely an easy and economic method to quantize ureidomustin in the biological samples. The aim of this study is to develop a simple yet valid quantization method to tackle this challenge.

Synthesis and antitumor evaluation of novel benzo[d]pyrrolo[2,1-b]thiazole derivatives.

A series of novel 2,3-bis(hydroxymethyl)benzo[d]pyrrolo[2,1-b]thiazoles and their bis(alkylcarbamate) derivatives were synthesized starting from benzothiazole via reaction with dimethyl acetylenedicarboxylate (DMAD)/tetra-fluoro boric acid, catalytic hydrogenation, and alkylcarbamoylation. The anti-proliferative activity of these agents against human leukemia and various solid tumor cell growth in vitro was studied. The structure-activity relationship studies revealed that the bis(alkylcarbamates) derivatives are generally more cytotoxic than the corresponding bis(hydroxymethyl) congeners in inhibiting human lymphoblastic leukemia CCRF-CEM and various human solid tumor cell growth in culture.

Novel 2-substituted quinolin-4-yl-benzenesulfonate derivatives: synthesis, antiproliferative activity, and inhibition of cellular tubulin polymerization.

A series of 2-substituted quinolin-4-yl-benzenesulfonate derivatives were synthesized for the purpose of evaluating antiproliferative activity. Structure-activity relationships of the newly synthesized compounds against human lymphoblastic leukemia and various solid tumor cell growths in culture are discussed. Of these derivatives, 2-phenyl-6-pyrrolidinyl-4-quinoline sulfonate analogues 10 f, 10 g, and 10 k, and 4'-nitrophenyl sulfonate 10 m exhibit superior cytotoxicity over other sulfonates.

The novel DNA alkylating agent BO-1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models.

Oral cancer is the fourth-most common cause of death in males and overall the sixth-most common cause of cancer death in Taiwan. Surgery, radiotherapy and chemotherapy combined with other therapies are the most common treatments for oral cavity cancer. Although cisplatin, 5-fluorouracil and docetaxel are commonly used clinically, there is no drug specific for oral cavity cancer.

Design, synthesis and antitumor evaluation of phenyl N-mustard-quinazoline conjugates.

A series of N-mustard-quinazoline conjugates was synthesized and subjected to antitumor studies. The N-mustard pharmacophore was attached at the C-6 of the 4-anilinoquinazolines via a urea linker. To study the structure-activity relationships of these conjugates, various substituents were introduced to the C-4 anilino moiety.

Novel bifunctional alkylating agents, 5,10-dihydropyrrolo[1,2-b]isoquinoline derivatives, synthesis and biological activity.

A series of linear pyrrolo[1,2-b]isoquinoline derivatives was synthesized for antitumor evaluation. The preliminary antitumor studies reveal that both bis(hydroxymethyl) and their bis(alkylcarbamate) derivatives show significant antitumor activity in inhibiting various human tumor cell growth in vitro. 1,2-Bis(hydroxymethyl)-3-methyl-5,10-dihydropyrrolo[1,2-b]isoquinoline (20a) was selected for antitumor studies in animal models.

Design, synthesis, and biological evaluation of novel water-soluble N-mustards as potential anticancer agents.

A series of novel water-soluble N-mustard-benzene conjugates bearing a urea linker were synthesized. The benzene moiety contains various hydrophilic side chains are linked to the meta- or para-position of the urea linker via a carboxamide or an ether linkage. The preliminary antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro and therapeutic efficacy against human tumor xenografts in vivo.

Combination of bifunctional alkylating agent and arsenic trioxide synergistically suppresses the growth of drug-resistant tumor cells.

Drug resistance is a crucial factor in the failure of cancer chemotherapy. In this study, we explored the effect of combining alkylating agents and arsenic trioxide (ATO) on the suppression of tumor cells with inherited or acquired resistance to therapeutic agents. Our results showed that combining ATO and a synthetic derivative of 3a-aza-cyclopenta[a]indenes (BO-1012), a bifunctional alkylating agent causing DNA interstrand cross-links, was more effective in killing human cancer cell lines (H460, H1299, and PC3) than combining ATO and melphalan or thiotepa.

Potent DNA-directed alkylating agents: Synthesis and biological activity of phenyl N-mustard-quinoline conjugates having a urea or hydrazinecarboxamide linker.

A series of N-mustard-quinoline conjugates bearing a urea or hydrazinecarboxamide linker was synthesized for antitumor evaluation. The in vitro cytotoxicity studies revealed that compounds with hydrazinecarboxamide linkers were generally more cytotoxic than the corresponding urea counterparts in inhibiting human lymphoblastic leukemia and various solid tumor cell growths in culture. The therapeutic efficacy against human tumor xenografts in animal model was studied.

Potent antitumor bifunctional DNA alkylating agents, synthesis and biological activities of 3a-aza-cyclopenta[a]indenes.

A series of bifunctional DNA interstrand cross-linking agents, bis(hydroxymethyl)- and bis(carbamates)-8H-3a-azacyclopenta[a]indene-1-yl derivatives were synthesized for antitumor evaluation. The preliminary antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro and antitumor therapeutic efficacy against human tumor xenografts in vivo. Furthermore, these derivatives have little or no cross-resistance to either Taxol or Vinblastine.

Synthesis and in vitro cytotoxicity of 9-anilinoacridines bearing N-mustard residue on both anilino and acridine rings.

A series of 9-anilinoacridines having an alkylating N-mustard pharmacophore on both anilino (C-3' or C-4') and acridine (C-4) rings with O-ethyl (O-C(2)) or O-butyl (O-C(4)) spacer were synthesized to evaluate their cytotoxicity against human lymphoblastic leukemia (CCRF-CEM) cell growth in vitro. It was revealed that these conjugates exhibited significant in vitro cytotoxicity. Among these agents, compound 13 was the most cytotoxic with IC(50) value of 1.

Synthesis and biological activity of stable and potent antitumor agents, aniline nitrogen mustards linked to 9-anilinoacridines via a urea linkage.

To improve the chemical stability and therapeutic efficacy of N-mustard, a series of phenyl N-mustard linked to DNA-affinic 9-anilinoacridines and acridine via a urea linker were synthesized and evaluated for antitumor studies. The new N-mustard derivatives were prepared by the reaction of 4-bis(2-chloroethyl)aminophenyl isocyanate with a variety of 9-anilinoacridines or 9-aminoacridine. The antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro without cross-resistance to taxol or vinblastine and showed potent antitumor therapeutic efficacy in nude mice against human tumor xenografts.