Three men at the heart of President Assad's defence team have died in a suicide bombing, Syrian state TV has reported.
The president's defence minister, brother-in-law and head of his crisis team were at a meeting at national security headquarters in Damascus.
No footage has yet emerged of the attack in which the national security chief and interior minister were also said to have been wounded.
It comes as rebels claim to have launched an offensive on the capital.
For the past three days, rebels have fought with troops in several parts of the city, declaring their operation, entitled Damascus Volcano, a final battle for the capital.
The rebel Free Syrian Army (FSA) and a jihadist group calling itself Lord of the Martyrs Brigade both said they were behind the security headquarters bombing.
Security sources say the suspected bomber worked as a bodyguard for members of President Bashar al-Assad's inner circle.
As events in Damascus unfolded, a UN Security Council vote on a Western-sponsored resolution threatening Syria with tougher sanctions was postponed until Thursday following a request by UN and Arab League envoy Kof Annan.
"The terrorist explosion which targeted the national security building in Damascus occurred during a meeting of ministers and a number of heads of security agencies," state TV said.
However, reporters in Damascus say none of the windows of the building appears to be broken and there is no sign of extra security.
The three murdered ministers are as follows:
General Daoud Rajiha had been defence minister for less than a year, serving previously as chief of staff, and was on a US blacklist for his role in the suppression of dissent.
He was believed to be an Orthodox Christian - a rarity in the Alawite-dominated Syrian military and government.
General Assef Shawkat was married to Mr Assad's sister Bushra and considered a top security chief and a member of the inner circle of the regime.
General Hassan Turkomani was a former defence minister and assistant to the vice president as well as being in charge of President Assad's crisis management office.
A long-standing senior member of the ruling Baath party and a Sunni Muslim, unlike many in the Syrian elite, he was put in charge of the security forces' crisis team when the uprising began in 2011, opposition activists said.
Hisham Ikhtiar, director of the National Security Bureau, and Interior Minister Mohammad Ibrahim al-Shaar, were also among those hurt in the attack, state TV said.
An armed forces' statement read out on TV said Syria was "more determined than ever" to fight terrorism and wipe out "criminal gangs".
Whoever thinks that killing top commanders "can twist Syria's arm...
is delusional", it said.
Reports however say, the rebels now clearly believe victory is within sight, and the deaths will give them even greater heart.
Earlier, activists reported more clashes during the night in several areas around the south-west of Damascus.
They said the government had brought more troops and armour into some districts, and that several people had been killed in clashes and bombardments.
Activists have also posted on the internet pictures of what they say is a barracks on the heights overlooking the city engulfed in flames.
They believed it had been hit by fire from FSA rebels, and said the barracks was involved in providing security for the presidential palace complex below.
State media said security forces fought off attacks by small groups of armed terrorists in the city.
Foreign journalists are however under heavy restrictions in Syria, making it difficult to verify the claims of either side.
Opposition groups say as many as 16,000 people have died in Syria since protests against President Assad began in March last year.